研究者詳細

顔写真

モリタ　マサノブ
守田　匡伸
Masanobu Morita
所属
大学院医学系研究科　公衆衛生学専攻　公共健康医学講座（環境医学分野）
職名
講師
学位

  • 博士（理学）

経歴 4

  • 2001年 ～ 2008年
    The Salk Institute, Research Associate

  • 1999年 ～ 2001年
    東北大学大学院理学研究科 未来開拓学術研究員

  • 2019年 ～
    東北大学大学院医学系研究科 講師

  • 2009年 ～
    東北大学大学院医学系研究科 助教

学歴 2

  • 東北大学理学研究科博士課程

    ～ 1999年3月

  • 東北大学理学部化学第二学科

    ～ 1994年3月

研究分野 1

  • ライフサイエンス / 分子生物学 /

論文 55

  1. Dual-color membrane-type immunoglobulin-directed hybridoma screening for selective and accelerated monoclonal antibody production.

    Mei Kawamura, Fujino Kuba, Atsumi Sakaguchi, Kosei Oishi, Tomoya Sugiyama, Wakana Ujiie, Soushi Murayama, Yusuke Fujisawa, Sayaka Kikuchi, Yoichiro Tanaka, Minkyung Jung, Masanobu Morita, Takaaki Akaike, Yasuyuki Kurihara

    Journal of bioscience and bioengineering　2026年2月4日

    DOI： 10.1016/j.jbiosc.2026.01.004 　

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    Monoclonal antibodies (mAbs) are essential tools in life sciences and medicine because they provide high specificity and selective binding properties. However, their production is labor-intensive. Conventional hybridoma screening using the limiting dilution method requires repeated manual handling and long-term culture, which slows the isolation of target antibodies. To facilitate this process, we previously developed a membrane-type immunoglobulin-directed hybridoma screening (MIHS) method that directly detects interactions between membrane-bound B-cell receptors and fluorescently labeled antigens. However, the preparation of multiple soluble antigens remains a challenge. Hence, we designed a single recombinant antigen, X-His-BAP-MBP (X-HBM), in which the target antigen (X) was fused to a solubilization tag (MBP), biotinylation tag (BAP), and His-tag for purification. We established a dual-color MIHS system that integrates immunization, screening, and evaluation into a workflow. Dual-color fluorescence labeling enabled the discrimination and exclusion of hybridomas producing antibodies against MBP or tag sequences, allowing the precise isolation of hybridomas secreting antibodies specific to the target antigen. Using the mitochondrial enzyme CARS2 as a model antigen, the proportion of target-positive hybridomas increased approximately eightfold compared to that using the conventional method. Specific mAbs were successfully obtained using only a single soluble antigen preparation through the MIHS method. This method supports the efficient selection of antigen-specific hybridomas, even when solubilization tags are used, by achieving both antigen specificity and practical solubility.

  2. Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors. 国際誌

    Eunkyu Sung, Shohei Murakami, Masanobu Morita, Tomoaki Ida, Takaaki Akaike, Hozumi Motohashi

    Stem cell reports　20　(12)　102720-102720　2025年12月9日

    DOI： 10.1016/j.stemcr.2025.102720 　

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    Recent studies highlight the critical role of mitochondria in hematopoiesis, especially in stem cell function and erythroid maturation. To explore mitochondrial contributions to cell lineage commitment of hematopoietic progenitors, we utilized Cars2-mutant mice, an ideal model for this purpose. CARS2, a mitochondrial isoform of cysteinyl-tRNA synthetase, has cysteine persulfide synthase (CPERS) activity. Our new mouse model, with reduced CPERS activity, showed that the Cars2 mutation led to mitochondrial inhibition and anemia by suppressing erythroid commitment in megakaryocyte-erythroid progenitors (MEPs). This suppression was reproduced using mitochondrial electron transport chain inhibitors. We identified two distinct MEP populations based on the mitochondrial content: mitochondria-rich MEPs favored erythroid differentiation, while the mitochondria-poor MEPs favored megakaryocyte differentiation. These findings reveal critical contributions of mitochondria to the MEP lineage selection, acting as a "mitochondrial navigation" for lineage commitment.

  3. Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release. 国際誌

    Chun-Yu Fu, Joshua B Kohl, Filip Liebsch, Davide D'Andrea, Tamás Ditrói, Seiryo Ogata, Franziska Neuser, Max Mai, Anna T Mellis, Emilia Kouroussis, Masanobu Morita, Titus Gehling, José Angel Santamaria-Araujo, Sin Yuin Yeo, Heike Endepols, Michaela Křížková, Viktor Kozich, Marcus Krueger, Julia B Hennermann, Uladzimir Barayeu, Takaaki Akaike, Peter Nagy, Milos Filipovic, Guenter Schwarz

    The Journal of clinical investigation　135　(21)　2025年11月3日

    DOI： 10.1172/JCI181299 　

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    Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.

  4. Sex-dependent epigenetic disruption of YY1 binding by prenatal BPA exposure downregulates Matr3 and alters Agap1 splicing in the offspring hippocampus. 国際誌

    Pattanachat Lertpeerapan, Songphon Kanlayaprasit, Surangrat Thongkorn, Kasidit Kasitipradit, Pawinee Panjabud, Kwanjira Songsritaya, Thanawin Jantheang, Masanobu Morita, Takaaki Akaike, Valerie W Hu, Depicha Jindatip, Thanit Saeliw, Tewarit Sarachana

    Biology of sex differences　16　(1)　63-63　2025年8月11日

    DOI： 10.1186/s13293-025-00744-1 　

  5. Supersulfides contribute to joint homeostasis and bone regeneration. 国際誌

    Miki Maemura, Masanobu Morita, Seiryo Ogata, Yoichi Miyamoto, Tomoaki Ida, Kazuhiro Shibusaka, Soichiro Negishi, Masahiro Hosonuma, Taku Saito, Jun Yoshitake, Tsuyoshi Takata, Tetsuro Matsunaga, Eikan Mishima, Uladzimir Barayeu, Takaaki Akaike, Fumiko Yano

    Redox biology　81　103545-103545　2025年2月11日

    DOI： 10.1016/j.redox.2025.103545 　

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    The physiological functions of supersulfides, inorganic and organic sulfides with sulfur catenation, have been extensively studied. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulfide synthase. This study aimed to investigate the role of supersulfides in joint homeostasis and bone regeneration. Using Cars2AINK/+ mutant mice, in which the KIIK motif of CARS2 essential for supersulfide production was replaced with AINK, we evaluated the role of supersulfides in fracture healing and cartilage homeostasis during osteoarthritis (OA). Tibial fracture surgery was performed on the wild-type (Cars2+/+) and Cars2AINK/+ mice littermates. Bulk RNA-seq analysis for the osteochondral regeneration in the fracture model showed increased inflammatory markers and reduced osteogenic factors, indicative of impaired bone regeneration, in Cars2AINK/+ mice. Destabilization of the medial meniscus (DMM) surgery was performed to produce the mouse OA model. Histological analyses with Osteoarthritis Research Society International and synovitis scores revealed accelerated OA progression in Cars2AINK/+ mice compared with that in Cars2+/+ mice. To assess the effects of supersulfides on OA progression, glutathione trisulfide (GSSSG) or saline was periodically injected into the mouse knee joints after the DMM surgery. Thus, supersulfides derived from CARS2 and GSSSG exogenously administered significantly inhibited inflammation and lipid peroxidation of the joint cartilage, possibly through suppression of ferroptosis, during OA development. This study represents a significant advancement in understanding anti-inflammatory and anti-oxidant functions of supersulfides in skeletal tissues and may have a clinical relevance for the bone healing and OA therapeutics.

  6. Supersulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation. 国際誌

    Shunichi Tayama, Yuya Kitamura, Kyoga Hiraide, Hibiki Suzuki, Jing Li, Ziying Yang, Ryoji Mitsuwaka, Akihisa Kawajiri, Kosuke Sato, Feng Gao, Taku Nakai, Yuko Okuyama, Tadahisa Numakura, Mitsuhiro Yamada, Tomoaki Ida, Masanobu Morita, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii

    Frontiers in immunology　16　1506580-1506580　2025年

    DOI： 10.3389/fimmu.2025.1506580 　

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    Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation where CD4+ T lymphocytes play an essential role. Accumulating evidence suggests that immune responses driven by CD4+ T cells are critically regulated by various metabolic pathways including oxidative phosphorylation and glycolysis. Here we show that CARS2/CPERS-dependent supersulfide metabolism restrains CD4+ T cell proliferation in a cell-intrinsic manner. Under steady state, Cars2 +/- mice exhibited spontaneous accumulation of effector/memory CD4+ T cells in the colon with age. In lymphopenic conditions, Cars2 +/- CD4+ T cells showed enhanced cell cycle entry with reduced expression of a cell cycle inhibitor Trp53 and triggered an exacerbated form of colitis, the response being rescued by treatment with a supersulfide donor glutathione trisulfide (GSSSG). Furthermore, re-analysis of publicly available gene datasets of human colonic CD4+ T lymphocytes revealed that downregulation of CARS2 was associated with pathogenesis of IBD, and indeed, addition of GSSSG inhibited human CD4+ T cell proliferation in vitro. Together these observations reveal that CARS2/CPERS-dependent supersulfide metabolism is essential for homeostasis of intestinal effector/memory CD4+ T cells, and further suggest that dysregulation of the same metabolic pathway can lead to development of gut inflammation both in mice and humans.

  7. New aspects of redox signaling mediated by supersulfides in health and disease. 国際誌

    Takaaki Akaike, Masanobu Morita, Seiryo Ogata, Jun Yoshitake, Minkyung Jung, Hiroki Sekine, Hozumi Motohashi, Uladzimir Barayeu, Tetsuro Matsunaga

    Free radical biology & medicine　222　539-551　2024年7月9日

    DOI： 10.1016/j.freeradbiomed.2024.07.007 　

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    Oxygen molecules accept electrons from the respiratory chain in the mitochondria and are responsible for energy production in aerobic organisms. The reactive oxygen species formed via these oxygen reduction processes undergo complicated electron transfer reactions with other biological substances, which leads to alterations in their physiological functions and cause diverse biological and pathophysiological consequences (e.g., oxidative stress). Oxygen accounts for only a small proportion of the redox reactions in organisms, especially under aerobic or hypoxic conditions but not under anaerobic and hypoxic conditions. This article discusses a completely new concept of redox biology, which is governed by redox-active supersulfides, i.e., sulfur-catenated molecular species. These species are present in abundance in all organisms but remain largely unexplored in terms of redox biology and life science research. In fact, accumulating evidence shows that supersulfides have extensive redox chemical properties and that they can be readily ionized or radicalized to participate in energy metabolism, redox signaling, and oxidative stress responses in cells and in vivo. Thus, pharmacological intervention and medicinal modulation of supersulfide activities have been shown to benefit the regulation of disease pathogenesis as well as disease control.

  8. Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism. 国際誌

    Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B Bloch, Takaaki Akaike, Fumito Ichinose

    The Journal of clinical investigation　2024年6月13日

    DOI： 10.1172/JCI170994 　

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    Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogens sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Administration of metronidazole or a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.

  9. Bag1 protein loss sensitizes mouse embryonic fibroblasts to glutathione depletion. 国際誌

    Atsushi Inose-Maruyama, Hayato Irokawa, Kouki Takeda, Keiko Taguchi, Masanobu Morita, Masayuki Yamamoto, Masato Sasaki, Shusuke Kuge

    Cell stress & chaperones　29　(3)　497-509　2024年6月

    DOI： 10.1016/j.cstres.2024.05.003 　

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    Bcl2-associated athanogene-1 protein (Bag1) acts as a co-chaperone of heat shock protein 70 and heat shock cognate 70 and regulates multiple cellular processes, including cell proliferation, apoptosis, environmental stress response, and drug resistance. Since Bag1 knockout mice exhibited fetal lethality, the in vivo function of Bag1 remains unclear. In this study, we established a mouse line expressing Bag1 gene missing exon 5, which corresponds to an encoding region for the interface of heat shock protein 70/heat shock cognate 70. Despite mice carrying homoalleles of the Bag1 mutant (Bag1Δex5) expressing undetectable levels of Bag1, Bag1Δex5 homozygous mice developed without abnormalities. Bag1Δex5 protein was found to be highly unstable in cells and in vitro. We found that the growth of mouse embryonic fibroblasts derived from Bag1Δex5-homo mice was attenuated by doxorubicin and a glutathione (GSH) synthesis inhibitor, buthionine sulfoximine. In response to buthionine sulfoximine, Bag1Δex5-mouse embryonic fibroblasts exhibited a higher dropping rate of GSH relative to the oxidized glutathione level. In addition, Bag1 might mitigate cellular hydrogen peroxide levels. Taken together, our results demonstrate that the loss of Bag1 did not affect mouse development and that Bag1 is involved in intracellular GSH homeostasis, namely redox homeostasis.

  10. Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function 査読有り

    Jun Takahashi, Takafumi Suzuki, Miu Sato, Shuji Nitta, Nahoko Yaguchi, Tatsuki Muta, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Shin Hamada, Atsushi Masamune, Satoru Takahashi, Takashi Kamei, Masayuki Yamamoto

    Cell Reports　2024年4月

    DOI： 10.1016/j.celrep.2024.114104 　

  11. 2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels. 国際誌

    Qi Cui, Meg Shieh, Tony W Pan, Akiyuki Nishimura, Tetsuro Matsunaga, Shane S Kelly, Shi Xu, Minkyung Jung, Seiryo Ogata, Masanobu Morita, Jun Yoshitake, Xiaoyan Chen, Jerome R Robinson, Wei-Jun Qian, Motohiro Nishida, Takaaki Akaike, Ming Xian

    Nature communications　15　(1)　2453-2453　2024年3月19日

    DOI： 10.1038/s41467-024-46652-7 　

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    Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

  12. Longevity control by supersulfide-mediated mitochondrial respiration and regulation of protein quality. 国際誌

    Akira Nishimura, Sunghyeon Yoon, Tetsuro Matsunaga, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Masanobu Morita, Jun Yoshitake, Yuka Unno, Uladzimir Barayeu, Tsuyoshi Takata, Hiroshi Takagi, Hozumi Motohashi, Albert van der Vliet, Takaaki Akaike

    Redox biology　69　103018-103018　2024年1月3日

    DOI： 10.1016/j.redox.2023.103018 　

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    Supersulfides, which are defined as sulfur species with catenated sulfur atoms, are increasingly being investigated in biology. We recently identified pyridoxal phosphate (PLP)-dependent biosynthesis of cysteine persulfide (CysSSH) and related supersulfides by cysteinyl-tRNA synthetase (CARS). Here, we investigated the physiological role of CysSSH in budding yeast (Saccharomyces cerevisiae) by generating a PLP-binding site mutation K109A in CRS1 (the yeast ortholog of CARS), which decreased the synthesis of CysSSH and related supersulfides and also led to reduced chronological aging, effects that were associated with an increased endoplasmic reticulum stress response and impaired mitochondrial bioenergetics. Reduced chronological aging in the K109A mutant could be rescued by using exogenous supersulfide donors. Our findings indicate important roles for CARS in the production and metabolism of supersulfides-to mediate mitochondrial function and to regulate longevity.

  13. Supersulfides support bone growth by promoting chondrocyte proliferation in the growth plates 国際誌

    Yuji Sasama, Kentaro Yoshimura, Marie Hoshino, Kiyohito Sasa, Takaaki Akaike, Masanobu Morita, Kazuyoshi Baba, Tatsuo Shirota, Yoichi Miyamoto

    Journal of Oral Biosciences　66　(1)　76-81　2023年11月

    出版者・発行元： Elsevier BV

    DOI： 10.1016/j.job.2023.11.004 　

    ISSN：1349-0079

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    OBJECTIVES: While chondrocytes have mitochondria, they receive little O2 from the bloodstream. Sulfur respiration, an essential energy production system in mitochondria, uses supersulfides instead of O2. Supersulfides are inorganic and organic sulfides with catenated sulfur atoms and are primarily produced by cysteinyl tRNA synthetase-2 (CARS2). Here, we investigated the role of supersulfides in chondrocyte proliferation and bone growth driven by growth plate chondrocyte proliferation. METHODS: We examined the effects of NaHS, an HS-/H2S donor, and cystine, the cellular source of cysteine, on the proliferation of mouse primary chondrocytes and growth of embryonic mouse tibia in vitro. We also examined the effect of RNA interference acting on the Cars2 gene on chondrocyte proliferation in the presence of cystine. RESULTS: NaHS (30 μmol/L) enhanced tibia longitudinal growth in vitro with expansion of the proliferating zone of their growth plates. While NaHS (30 μmol/L) also promoted chondrocyte proliferation only under normoxic conditions (20 % O2), cystine (0.5 mmol/L) promoted it under both normoxic and hypoxic (2 % O2) conditions. Cars2 gene knockdown abrogated the ability of cystine (0.5 mmol/L) to promote chondrocyte proliferation under normoxic conditions, indicating that supersulfides produced by CARS2 were responsible for the cystine-dependent promotion of bone growth. CONCLUSIONS: The presented results indicate that supersulfides play a vital role in bone growth achieved by chondrocyte proliferation in the growth plates driven by sulfur respiration.

  14. Supersulfide catalysis for nitric oxide and aldehyde metabolism. 国際誌

    Shingo Kasamatsu, Akira Nishimura, Md Morshedul Alam, Masanobu Morita, Kakeru Shimoda, Tetsuro Matsunaga, Minkyung Jung, Seiryo Ogata, Uladzimir Barayeu, Tomoaki Ida, Motohiro Nishida, Akiyuki Nishimura, Hozumi Motohashi, Takaaki Akaike

    Science advances　9　(33)　eadg8631　2023年8月18日

    DOI： 10.1126/sciadv.adg8631 　

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    Abundant formation of endogenous supersulfides, which include reactive persulfide species and sulfur catenated residues in thiols and proteins (supersulfidation), has been observed. We found here that supersulfides catalyze S-nitrosoglutathione (GSNO) metabolism via glutathione-dependent electron transfer from aldehydes by exploiting alcohol dehydrogenase 5 (ADH5). ADH5 is a highly conserved bifunctional enzyme serving as GSNO reductase (GSNOR) that down-regulates NO signaling and formaldehyde dehydrogenase (FDH) that detoxifies formaldehyde in the form of glutathione hemithioacetal. C174S mutation significantly reduced the supersulfidation of ADH5 and almost abolished GSNOR activity but spared FDH activity. Notably, Adh5C174S/C174S mice manifested improved cardiac functions possibly because of GSNOR elimination and consequent increased NO bioavailability. Therefore, we successfully separated dual functions (GSNOR and FDH) of ADH5 (mediated by the supersulfide catalysis) through the biochemical analysis for supersulfides in vitro and characterizing in vivo phenotypes of the GSNOR-deficient organisms that we established herein. Supersulfides in ADH5 thus constitute a substantial catalytic center for GSNO metabolism mediating electron transfer from aldehydes.

  15. Persulfide Biosynthesis Conserved Evolutionarily in All Organisms

    Seiryo Ogata, Tetsuro Matsunaga, Minkyung Jung, Uladzimir Barayeu, Masanobu Morita, Takaaki Akaike

    Antioxidants & Redox Signaling　2023年8月11日

    出版者・発行元： Mary Ann Liebert Inc

    DOI： 10.1089/ars.2023.0405 　

    ISSN：1523-0864

    eISSN：1557-7716

  16. Supersulphides provide airway protection in viral and chronic lung diseases. 国際誌

    Tetsuro Matsunaga, Hirohito Sano, Katsuya Takita, Masanobu Morita, Shun Yamanaka, Tomohiro Ichikawa, Tadahisa Numakura, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Sunghyeon Yoon, Naoya Fujino, Yorihiko Kyogoku, Yusaku Sasaki, Akira Koarai, Tsutomu Tamada, Atsuhiko Toyama, Takakazu Nakabayashi, Lisa Kageyama, Shigeru Kyuwa, Kenji Inaba, Satoshi Watanabe, Péter Nagy, Tomohiro Sawa, Hiroyuki Oshiumi, Masakazu Ichinose, Mitsuhiro Yamada, Hisatoshi Sugiura, Fan-Yan Wei, Hozumi Motohashi, Takaaki Akaike

    Nature communications　14　(1)　4476-4476　2023年7月25日

    DOI： 10.1038/s41467-023-40182-4 　

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    Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease.

  17. Synthesis of Sulfides and Persulfides Is Not Impeded by Disruption of Three Canonical Enzymes in Sulfur Metabolism. 国際誌

    Qamarul Hafiz Zainol Abidin, Tomoaki Ida, Masanobu Morita, Tetsuro Matsunaga, Akira Nishimura, Minkyung Jung, Naim Hassan, Tsuyoshi Takata, Isao Ishii, Warren Kruger, Rui Wang, Hozumi Motohashi, Masato Tsutsui, Takaaki Akaike

    Antioxidants (Basel, Switzerland)　12　(4)　2023年4月3日

    DOI： 10.3390/antiox12040868 　

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    Reactive sulfur species, or persulfides and polysulfides, such as cysteine hydropersulfide and glutathione persulfide, are endogenously produced in abundance in both prokaryotes and eukaryotes, including mammals. Various forms of reactive persulfides occur in both low-molecular-weight and protein-bound thiols. The chemical properties and great supply of these molecular species suggest a pivotal role for reactive persulfides/polysulfides in different cellular regulatory processes (e.g., energy metabolism and redox signaling). We demonstrated earlier that cysteinyl-tRNA synthetase (CARS) is a new cysteine persulfide synthase (CPERS) and is responsible for the in vivo production of most reactive persulfides (polysulfides). Some researchers continue to suggest that 3-mercaptopyruvate sulfurtransferase (3-MST), cystathionine β-synthase (CBS), and cystathionine γ-lyase (CSE) may also produce hydrogen sulfide and persulfides that may be generated during the transfer of sulfur from 3-mercaptopyruvate to the cysteine residues of 3-MST or direct synthesis from cysteine by CBS/CSE, respectively. We thus used integrated sulfur metabolome analysis, which we recently developed, with 3-MST knockout (KO) mice and CBS/CSE/3-MST triple-KO mice, to elucidate the possible contribution of 3-MST, CBS, and CSE to the production of reactive persulfides in vivo. We therefore quantified various sulfide metabolites in organs derived from these mutant mice and their wild-type littermates via this sulfur metabolome, which clearly revealed no significant difference between mutant mice and wild-type mice in terms of reactive persulfide production. This result indicates that 3-MST, CBS, and CSE are not major sources of endogenous reactive persulfide production; rather, CARS/CPERS is the principal enzyme that is actually involved in and even primarily responsible for the biosynthesis of reactive persulfides and polysulfides in vivo in mammals.

  18. Cysteine hydropersulfide reduces lipid peroxidation and protects against myocardial ischaemia-reperfusion injury - Are endogenous persulfides mediators of ischaemic preconditioning? 国際誌

    Kayleigh Griffiths, Tomoaki Ida, Masanobu Morita, Reece J Lamb, Jordan J Lee, Michael P Frenneaux, Jon M Fukuto, Takaaki Akaike, Martin Feelisch, Melanie Madhani

    Redox biology　60　102605-102605　2023年1月10日

    DOI： 10.1016/j.redox.2023.102605 　

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    Earlier studies revealed the presence of cysteine persulfide (CysSSH) and related polysulfide species in various mammalian tissues. CysSSH has both antioxidant and oxidant properties, modulates redox-dependent signal transduction and has been shown to mitigate oxidative stress. However, its functional relevance in the setting of myocardial ischaemia-reperfusion injury (IRI) remains unknown. The present study was undertaken to (1) study the dynamics of production and consumption of persulfides under normoxic and hypoxic conditions in the heart, and (2) determine whether exogenous administration of the CysSSH donor, cysteine trisulfide (Cys-SSS-Cys) at the onset of reperfusion rescues functional impairment and myocardial damage by interfering with lipid peroxidation. Utilising a well-established ex vivo Langendorff murine model, we here demonstrate that endogenous tissue concentrations of CysSSH are upregulated when oxygen supply is compromised (global myocardial ischaemia) and rapidly restored to baseline levels upon reperfusion, suggestive of active regulation. In a separate set of experiments, exogenous administration of Cys-SSS-Cys for 10 min at the onset of reperfusion was found to decrease malondialdehyde (MDA) concentrations, formation of 4-hydroxynonenal (4-HNE) protein adducts and rescue the heart from injury. Cys-SSS-Cys also restored post-ischaemic cardiac function, improving both coronary flow and left ventricular developed pressure (LVDP). Taken together, these results support the notion that endogenous CysSSH plays an important role as a "redox preconditioning" agent to combat the oxidative insult in myocardial IRI.

  19. Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding

    Atsushi Hasegawa, Yuki Hayasaka, Masanobu Morita, Yuta Takenaka, Yuna Hosaka, Ikuo Hirano, Masayuki Yamamoto, Ritsuko Shimizu

    Communications Biology　5　(1)　2022年12月

    出版者・発行元： Springer Science and Business Media LLC

    DOI： 10.1038/s42003-022-03316-w 　

    eISSN：2399-3642

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    Abstract Accumulating lines of clinical evidence support the emerging hypothesis that loss-of-function mutations of GATA2 cause inherited hematopoietic diseases, including Emberger syndrome; dendritic cell, monocyte B and NK lymphoid (DCML) deficiency; and MonoMAC syndrome. Here, we show that mice heterozygous for an arginine-to-tryptophan substitution mutation in GATA2 (G2R398W/+), which was found in a patient with DCML deficiency, substantially phenocopy human DCML deficiency. Mice heterozygous for the GATA2-null mutation (G2-/+) do not show such phenotypes. The G2R398W protein possesses a decreased DNA-binding affinity but obstructs the function of coexpressed wild-type GATA2 through specific cis-regulatory regions, which contain two GATA motifs in direct-repeat arrangements. In contrast, G2R398W is innocuous in mice containing single GATA motifs. We conclude that the dominant-negative effect of mutant GATA2 on wild-type GATA2 through specific enhancer/silencer of GATA2 target genes perturbs the GATA2 transcriptional network, leading to the development of the DCML-like phenotype. The present mouse model provides an avenue for the understanding of molecular mechanisms underlying the pathogenesis of GATA2-related hematopoietic diseases.

  20. CD3鎖を標的とした超硫黄分子によるTCRシグナルを介した免疫応答制御

    守田 匡伸, 山田 充啓, 佐々木 優作, 井田 智章, 松永 哲郎, 高田 剛, 渡部 聡, 稲葉 謙次, 石井 直人, 杉浦 久敏, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　95回　3P-132　2022年11月

    出版者・発行元： (公社)日本生化学会

  21. CD3鎖を標的とした超硫黄分子によるTCRシグナルを介した免疫応答制御

    守田 匡伸, 山田 充啓, 佐々木 優作, 井田 智章, 松永 哲郎, 高田 剛, 渡部 聡, 稲葉 謙次, 石井 直人, 杉浦 久敏, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　95回　3P-132　2022年11月

    出版者・発行元： (公社)日本生化学会

  22. 8-Nitro-cGMP suppresses mineralization by mouse osteoblasts.

    Kotaro Kaneko, Yoichi Miyamoto, Tomoaki Ida, Masanobu Morita, Kentaro Yoshimura, Kei Nagasaki, Kazuki Toba, Risa Sugisaki, Hozumi Motohashi, Takaaki Akaike, Daichi Chikazu, Ryutaro Kamijo

    Journal of clinical biochemistry and nutrition　71　(3)　191-197　2022年11月

    DOI： 10.3164/jcbn.21-129 　

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    Nitric oxide and reactive oxygen species regulate bone remodeling, which occurs via bone formation and resorption by osteoblasts and osteoclasts, respectively. Recently, we found that 8-nitro-cGMP, a second messenger of nitric oxide and reactive oxygen species, promotes osteoclastogenesis. Here, we investigated the formation and function of 8-nitro-cGMP in osteoblasts. Mouse calvarial osteoblasts were found to produce 8-nitro-cGMP, which was augmented by tumor necrosis factor-α (10 ng/ml) and interleukin-1β (1 ng/ml). These cytokines suppressed osteoblastic differentiation in a NO synthase activity-dependent manner. Exogenous 8-nitro-cGMP (30 μmol/L) suppressed expression of osteoblastic phenotypes, including mineralization, in clear contrast to the enhancement of mineralization by osteoblasts induced by 8-bromo-cGMP, a cell membrane-permeable analog of cGMP. It is known that reactive sulfur species denitrates and degrades 8-nitro-cGMP. Mitochondrial cysteinyl-tRNA synthetase plays a crucial role in the endogenous production of RSS. The expression of osteoblastic phenotypes was suppressed by not only exogenous 8-nitro-cGMP but also by silencing of the Cars2 gene, indicating a role of endogenous 8-nitro-cGMP in suppressing the expression of osteoblastic phenotypes. These results suggest that 8-nitro-cGMP is a negative regulator of osteoblastic differentiation.

  23. T細胞受容体シグナルを標的とした超硫黄分子による免疫応答制御

    守田 匡伸, 山田 充啓, 佐々木 優作, 井田 智章, 松永 哲郎, 稲葉 謙次, 石井 直人, 杉浦 久敏, 本橋 ほづみ, 赤池 孝章

    日本細菌学雑誌　77　(1)　103-103　2022年2月

    出版者・発行元： 日本細菌学会

    ISSN：0021-4930

    eISSN：1882-4110

  24. Methods in sulfide and persulfide research

    Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Tomoaki Ida, Masanobu Morita, Hozumi Motohashi, Xinggui Shen, Christopher G. Kevil, Jon M. Fukuto, Takaaki Akaike

    Nitric Oxide　116　47-64　2021年11月

    出版者・発行元： Elsevier BV

    DOI： 10.1016/j.niox.2021.09.002 　

    ISSN：1089-8603

  25. Heparan sulfate promotes differentiation of white adipocytes to maintain insulin sensitivity and glucose homeostasis. 国際誌

    Takuro Matsuzawa, Masanobu Morita, Ai Shimane, Rina Otsuka, Yu Mei, Fumitoshi Irie, Yu Yamaguchi, Kazuhiko Yanai, Takeo Yoshikawa

    The Journal of biological chemistry　297　(3)　101006-101006　2021年7月24日

    DOI： 10.1016/j.jbc.2021.101006 　

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    Heparan sulfate (HS), a highly sulfated linear polysaccharide, is involved in diverse biological functions in various tissues. Although previous studies have suggested a possible contribution of HS to the differentiation of white adipocytes, there has been no direct evidence supporting this. Here, we inhibited the synthesis of HS chains in 3T3-L1 cells using CRISPR-Cas9 technology, resulting in impaired differentiation of adipocytes with attenuated bone morphogenetic protein 4 (BMP4)-fibroblast growth factor 1 (FGF1) signaling pathways. HS reduction resulted in reduced glucose uptake and decreased insulin-dependent intracellular signaling. We then made heterozygous mutant mice for the Ext1 gene, which encodes an enzyme essential for the HS biosynthesis, specifically in the visceral white adipose tissue (Fabp4-Cre+::Ext1flox/WT mice, hereafter called Ext1Δ/WT) to confirm the importance of HS in vivo. The expression levels of transcription factors that control adipocyte differentiation, such as peroxisome proliferator-activated receptor gamma, were reduced in Ext1Δ/WT adipocytes, which contained smaller, unilocular lipid droplets, reduced levels of enzymes involved in lipid synthesis, and altered expression of BMP4-FGF1 signaling molecules. Furthermore, we examined the impact of HS reduction in visceral white adipose tissue on systemic glucose homeostasis. We observed that Ext1Δ/WT mice showed glucose intolerance because of insulin resistance. Our results demonstrate that HS plays a crucial role in the differentiation of white adipocytes through BMP4-FGF1 signaling pathways, thereby contributing to insulin sensitivity and glucose homeostasis.

  26. Sulfide catabolism ameliorates hypoxic brain injury. 国際誌

    Eizo Marutani, Masanobu Morita, Shuichi Hirai, Shinichi Kai, Robert M H Grange, Yusuke Miyazaki, Fumiaki Nagashima, Lisa Traeger, Aurora Magliocca, Tomoaki Ida, Tetsuro Matsunaga, Daniel R Flicker, Benjamin Corman, Naohiro Mori, Yumiko Yamazaki, Annabelle Batten, Rebecca Li, Tomohiro Tanaka, Takamitsu Ikeda, Akito Nakagawa, Dmitriy N Atochin, Hideshi Ihara, Benjamin A Olenchock, Xinggui Shen, Motohiro Nishida, Kenjiro Hanaoka, Christopher G Kevil, Ming Xian, Donald B Bloch, Takaaki Akaike, Allyson G Hindle, Hozumi Motohashi, Fumito Ichinose

    Nature communications　12　(1)　3108-3108　2021年5月25日

    DOI： 10.1038/s41467-021-23363-x 　

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    The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

  27. The establishment of a novel high-throughput screening system using RNA-guided genome editing to identify chemicals that suppress aldosterone synthase expression. 国際誌 査読有り

    Ryo Ito, Masanobu Morita, Taichi Nakano, Ikuko Sato, Atsushi Yokoyama, Akira Sugawara

    Biochemical and biophysical research communications　534　672-679　2021年1月1日

    DOI： 10.1016/j.bbrc.2020.11.020 　

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    Aldosterone is synthesized in the adrenal by the aldosterone synthase CYP11B2. Although the control of CYP11B2 expression is important to maintain the mineral homeostasis, its overexpression induced by the depolarization-induced calcium (Ca2+) signaling activation has been reported to increase the synthesis of aldosterone in primary aldosteronism (PA). The drug against PA focused on the suppression of CYP11B2 expression has not yet been developed, since the molecular mechanism of CYP11B2 transcriptional regulation activated via Ca2+ signaling remains unclear. To address the issue, we attempted to reveal the mechanism of the transcriptional regulation of CYP11B2 using chemical screening. We generated a cell line by inserting Nanoluc gene as a reporter into CYP11B2 locus in H295R adrenocortical cells using the CRSPR/Cas9 system, and established the high-throughput screening system using the cell line. We then identified 9 compounds that inhibited the CYP11B2 expression induced by potassium-mediated depolarization from the validated compound library (3399 compounds). Particularly, tacrolimus, an inhibitor of phosphatase calcineurin, strongly suppressed the CYP11B2 expression even at 10 nM. These results suggest that the system is effective in identifying drugs that suppress the depolarization-induced CYP11B2 expression. Our screening system may therefore be a useful tool for the development of novel medicines against PA.

  28. Production of IL-17A at Innate Immune Phase Leads to Decreased Th1 Immune Response and Attenuated Host Defense against Infection with Cryptococcus deneoformans. 国際誌

    Ko Sato, Hideki Yamamoto, Toshiki Nomura, Jun Kasamatsu, Tomomitsu Miyasaka, Daiki Tanno, Ikumi Matsumoto, Takafumi Kagesawa, Anna Miyahara, Tong Zong, Akiho Oniyama, Kotone Kawamura, Rin Yokoyama, Yuki Kitai, Shigenari Ishizuka, Emi Kanno, Hiromasa Tanno, Hiromi Suda, Masanobu Morita, Masayuki Yamamoto, Yoichiro Iwakura, Keiko Ishii, Kazuyoshi Kawakami

    Journal of immunology (Baltimore, Md. : 1950)　205　(3)　686-698　2020年8月1日

    DOI： 10.4049/jimmunol.1901238 　

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    IL-17A is a proinflammatory cytokine produced by many types of innate immune cells and Th17 cells and is involved in the elimination of extracellularly growing microorganisms, yet the role of this cytokine in the host defense against intracellularly growing microorganisms is not well known. Cryptococcus deneoformans is an opportunistic intracellular growth fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired immune responses. In the current study, we analyzed the role of IL-17A in the host defense against C. deneoformans infection. IL-17A was quickly produced by γδT cells at an innate immune phase in infected lungs. In IL-17A gene-disrupted mice, clearance of this fungal pathogen and the host immune response mediated by Th1 cells were significantly accelerated in infected lungs compared with wild-type mice. Similarly, killing of this fungus and production of inducible NO synthase and TNF-α were significantly enhanced in IL-17A gene-disrupted mice. In addition, elimination of this fungal pathogen, Th1 response, and expression of IL-12Rβ2 and IFN-γ in NK and NKT cells were significantly suppressed by treatment with rIL-17A. The production of IL-12p40 and TNF-α from bone marrow-derived dendritic cells stimulated with C. deneoformans was significantly suppressed by rIL-17A. In addition, rIL-17A attenuated Th1 cell differentiation in splenocytes from transgenic mice highly expressing TCR for mannoprotein 98, a cryptococcal Ag, upon stimulation with recombinant mannoprotein 98. These data suggest that IL-17A may be involved in the negative regulation of the local host defense against C. deneoformans infection through suppression of the Th1 response.

  29. Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells. 国際誌

    Akira Nishimura, Ryo Nasuno, Yuki Yoshikawa, Minkyung Jung, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hiroshi Takagi, Hozumi Motohashi, Takaaki Akaike

    The Journal of biological chemistry　294　(37)　13781-13788　2019年9月13日

    DOI： 10.1074/jbc.RA119.009203 　

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    Eukaryotes typically utilize two distinct aminoacyl-tRNA synthetase isoforms, one for cytosolic and one for mitochondrial protein synthesis. However, the genome of budding yeast (Saccharomyces cerevisiae) contains only one cysteinyl-tRNA synthetase gene (YNL247W, also known as CRS1). In this study, we report that CRS1 encodes both cytosolic and mitochondrial isoforms. The 5' complementary DNA end method and GFP reporter gene analyses indicated that yeast CRS1 expression yields two classes of mRNAs through alternative transcription starts: a long mRNA containing a mitochondrial targeting sequence and a short mRNA lacking this targeting sequence. We found that the mitochondrial Crs1 is the product of translation from the first initiation AUG codon on the long mRNA, whereas the cytosolic Crs1 is produced from the second in-frame AUG codon on the short mRNA. Genetic analysis and a ChIP assay revealed that the transcription factor heme activator protein (Hap) complex, which is involved in mitochondrial biogenesis, determines the transcription start sites of the CRS1 gene. We also noted that Hap complex-dependent initiation is regulated according to the needs of mitochondrial energy production. The results of our study indicate energy-dependent initiation of alternative transcription of CRS1 that results in production of two Crs1 isoforms, a finding that suggests Crs1's potential involvement in mitochondrial energy metabolism in yeast.

  30. Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. 国際誌 査読有り

    Takafumi Suzuki, Aki Muramatsu, Ryota Saito, Tatsuro Iso, Takahiro Shibata, Keiko Kuwata, Shin-Ichi Kawaguchi, Takao Iwawaki, Saki Adachi, Hiromi Suda, Masanobu Morita, Koji Uchida, Liam Baird, Masayuki Yamamoto

    Cell reports　28　(3)　746-758　2019年7月16日

    DOI： 10.1016/j.celrep.2019.06.047 　

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    The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.

  31. Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation. 国際誌

    Kei Saito, Tohru Fujiwara, Shunsuke Hatta, Masanobu Morita, Koya Ono, Chie Suzuki, Noriko Fukuhara, Yasushi Onishi, Yukio Nakamura, Shin Kawamata, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae

    Molecular and cellular biology　39　(7)　2019年4月1日

    DOI： 10.1128/MCB.00387-18 　

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    Ring sideroblasts are a hallmark of sideroblastic anemia, although little is known about their characteristics. Here, we first generated mutant mice by disrupting the GATA-1 binding motif at the intron 1 enhancer of the ALAS2 gene, a gene responsible for X-linked sideroblastic anemia (XLSA). Although heterozygous female mice showed an anemic phenotype, ring sideroblasts were not observed in their bone marrow. We next established human induced pluripotent stem cell-derived proerythroblast clones harboring the same ALAS2 gene mutation. Through coculture with sodium ferrous citrate, mutant clones differentiated into mature erythroblasts and became ring sideroblasts with upregulation of metal transporters (MFRN1, ZIP8, and DMT1), suggesting a key role for ferrous iron in erythroid differentiation. Interestingly, holo-transferrin (holo-Tf) did not induce erythroid differentiation as well as ring sideroblast formation, and mutant cells underwent apoptosis. Despite massive iron granule content, ring sideroblasts were less apoptotic than holo-Tf-treated undifferentiated cells. Microarray analysis revealed upregulation of antiapoptotic genes in ring sideroblasts, a profile partly shared with erythroblasts from a patient with XLSA. These results suggest that ring sideroblasts exert a reaction to avoid cell death by activating antiapoptotic programs. Our model may become an important tool to clarify the pathophysiology of sideroblastic anemia.

  32. Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis 査読有り

    Hisyam Abdul Hamid, Akira Tanaka, Tomoaki Ida, Akira Nishimura, Tetsuro Matsunaga, Shigemoto Fujii, Masanobu Morita, Tomohiro Sawa, Jon M. Fukuto, Péter Nagy, Ryouhei Tsutsumi, Hozumi Motohashi, Hideshi Ihara, Takaaki Akaike

    Redox Biology　21　101096　2019年2月

    DOI： 10.1016/j.redox.2019.101096 　

    ISSN：2213-2317

  33. Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo 国際誌 査読有り

    Eiki Yoshida, Takafumi Suzuki, Masanobu Morita, Keiko Taguchi, Kohei Tsuchida, Hozumi Motohashi, Minoru Doita, Masayuki Yamamoto

    Genes to Cells　23　(5)　386-392　2018年5月

    出版者・発行元： Wiley

    DOI： 10.1111/gtc.12579 　

    ISSN：1356-9597

  34. Cysteine Hydropersulfide Production Catalyzed by Cysteinyl-tRNA Synthetases 査読有り

    Tomoaki Ida, Akira Nishimura, Masanobu Morita, Hozumi Motohashi, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　112　189-190　2017年11月

    DOI： 10.1016/j.freeradbiomed.2017.10.297 　

    ISSN：0891-5849

    eISSN：1873-4596

  35. Moonlighting Functions of Cysteinyl-tRNA Synthetases: Cycteine Hydropersulfide Production and Regulation of Mitochondrial Biogenesis and Bioenergetics 査読有り

    Takaaki Akaike, Akira Nishimura, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hozumi Motohashi

    FREE RADICAL BIOLOGY AND MEDICINE　112　182-183　2017年11月

    DOI： 10.1016/j.freeradbiomed.2017.10.284 　

    ISSN：0891-5849

    eISSN：1873-4596

  36. Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. 国際誌 査読有り

    Takaaki Akaike, Tomoaki Ida, Fan-Yan Wei, Motohiro Nishida, Yoshito Kumagai, Md Morshedul Alam, Hideshi Ihara, Tomohiro Sawa, Tetsuro Matsunaga, Shingo Kasamatsu, Akiyuki Nishimura, Masanobu Morita, Kazuhito Tomizawa, Akira Nishimura, Satoshi Watanabe, Kenji Inaba, Hiroshi Shima, Nobuhiro Tanuma, Minkyung Jung, Shigemoto Fujii, Yasuo Watanabe, Masaki Ohmuraya, Péter Nagy, Martin Feelisch, Jon M Fukuto, Hozumi Motohashi

    Nature communications　8　(1)　1177-1177　2017年10月27日

    DOI： 10.1038/s41467-017-01311-y 　

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    Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate L-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction.

  37. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis 査読有り

    Eiko Sakai, Masanobu Morita, Masahiro Ohuchi, Mizuho A. Kido, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Ken Itoh, Masayuki Yamamoto, Takayuki Tsukuba

    FASEB JOURNAL　31　(9)　4011-4022　2017年9月

    DOI： 10.1096/fj.201700177R 　

    ISSN：0892-6638

    eISSN：1530-6860

  38. 細菌から哺乳類に至るまで保存されている硫化水素代謝酵素Sqrdlの遺伝子改変マウスを用いた機能解析

    守田 匡伸, 南嶋 洋司, 井田 智章, 松永 哲郎, 笠松 真吾, 西村 明, 藤井 重元, 市瀬 史, 赤池 孝章

    日本細菌学雑誌　72　(1)　98-98　2017年2月

    出版者・発行元： 日本細菌学会

    ISSN：0021-4930

    eISSN：1882-4110

  39. レドックスシグナルの活性イオウ分子制御

    笠松 真吾, 守田 匡伸, 赤池 孝章

    ファルマシア　53　(3)　210-214　2017年

    出版者・発行元： 公益社団法人 日本薬学会

    DOI： 10.14894/faruawpsj.53.3_210 　

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    活性酸素種（ROS）は、非特異的化学修飾をもたらす毒性因子としての側面の他に、生理的な細胞内シグナル（レドックスシグナル）分子としての機能を持つ。ROS・レドックスシグナルはその下流で生じる親電子物質を介して巧妙に制御されている。最近、新規レドックスシグナル制御因子として活性イオウ分子種が同定された。活性イオウ分子種によるレドックスシグナル制御機構の解析は、酸化ストレスの関わる疾病の新規予防・治療戦略の開発に寄与すると期待される。

  40. Redox Signaling Regulated by Cysteine Persulfide and Protein Polysulfidation 査読有り

    Shingo Kasamatsu, Akira Nishimura, Masanobu Morita, Tetsuro Matsunaga, Hisyam Abdul Hamid, Takaaki Akaike

    MOLECULES　21　(12)　2016年12月

    DOI： 10.3390/molecules21121721 　

    ISSN：1420-3049

  41. Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity. 国際誌

    Keiko Taguchi, Misaki Takaku, Patricia A Egner, Masanobu Morita, Takehito Kaneko, Tomoji Mashimo, Thomas W Kensler, Masayuki Yamamoto

    Toxicological sciences : an official journal of the Society of Toxicology　152　(1)　40-52　2016年7月

    DOI： 10.1093/toxsci/kfw065 　

    詳細を見る 詳細を閉じる

    THE TRANSCRIPTION FACTOR NRF2: (NF-E2-related-factor 2) REGULATES A BATTERY OF ANTIOXIDATIVE STRESS-RESPONSE GENES AND DETOXICATION GENES, AND NRF2 KNOCKOUT LINES OF MICE HAVE BEEN CONTRIBUTING CRITICALLY TO THE CLARIFICATION OF ROLES THAT NRF2 PLAYS FOR CELL PROTECTION HOWEVER, THERE ARE APPARENT LIMITATIONS IN USE OF THE MOUSE MODELS FOR INSTANCE, RATS EXHIBIT MORE SUITABLE FEATURES FOR TOXICOLOGICAL OR PHYSIOLOGICAL EXAMINATIONS THAN MICE IN THIS STUDY, WE GENERATED 2 LINES OF NRF2 KNOCKOUT RATS BY USING A GENOME EDITING TECHNOLOGY; 1 LINE HARBORS A 7-BP DELETION Δ7 AND THE OTHER LINE HARBORS A 1-BP INSERTION +1 IN THE NRF2 GENE IN THE LIVERS OF RATS HOMOZYGOUSLY DELETING THE NRF2 GENE, AN ACTIVATOR OF NRF2 SIGNALING, CDDO-IM, COULD NOT INDUCE EXPRESSION OF REPRESENTATIVE NRF2 TARGET GENES TO EXAMINE ALTERED TOXICOLOGICAL RESPONSE, WE TREATED THE NRF2 KNOCKOUT RATS WITH AFLATOXIN B1 AFB1, A CARCINOGENIC MYCOTOXIN THAT ELICITS GENE MUTATIONS THROUGH BINDING OF ITS METABOLITES TO DNA AND FOR WHICH THE RAT HAS BEEN PROPOSED AS A REASONABLE SURROGATE FOR HUMAN TOXICITY INDEED, IN THE NRF2 KNOCKOUT RAT LIVERS THE ENZYMES OF THE AFB1 DETOXICATION PATHWAY WERE SIGNIFICANTLY DOWNREGULATED SINGLE DOSE ADMINISTRATION OF AFB1 INCREASED HEPATOTOXICITY AND BINDING OF AFB1-N7-GUANINE TO HEPATIC DNA IN NRF2 KNOCKOUT RATS COMPARED WITH WILD-TYPE NRF2 KNOCKOUT RATS REPEATEDLY TREATED WITH AFB1 WERE PRONE TO LETHALITY AND CDDO-IM WAS NO LONGER PROTECTIVE THESE RESULTS DEMONSTRATE THAT NRF2 KNOCKOUT RATS ARE QUITE SENSITIVE TO AFB1 TOXICITIES AND THIS RAT GENOTYPE EMERGES AS A NEW MODEL ANIMAL IN TOXICOLOGY.

  42. Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection 査読有り

    Akihito Otsuki, Mikiko Suzuki, Fumiki Katsuoka, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Ritsuko Shimizu, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　91　45-57　2016年2月

    DOI： 10.1016/j.freeradbiomed.2015.12.005 　

    ISSN：0891-5849

    eISSN：1873-4596

  43. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response 査読有り

    Ryota Saito, Takafumi Suzuki, Keiichiro Hiramoto, Soichiro Asami, Eriko Naganuma, Hiromi Suda, Tatsuro Iso, Hirotaka Yamamoto, Masanobu Morita, Liam Baird, Yuki Furusawa, Takaaki Negishi, Masakazu Ichinose, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　36　(2)　271-284　2016年1月

    DOI： 10.1128/MCB.00868-15 　

    ISSN：0270-7306

    eISSN：1098-5549

  44. UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice. 査読有り

    Ainoya Keiko, Moriguchi Takashi, Ohmori Shin'ya, Souma Tomokazu, Takai Jun, Morita Masanobu, Chandler Kelly J, Mortlock Douglas P, Shimizu Ritsuko, Engel James Douglas, Lim Kim-Chew, Yamamoto Masayuki

    Mol Cell Biol　32　(12)　2312-2322　2012年6月

    DOI： 10.1128/MCB.06699-11 　

  45. Survival Strategy and Disease Pathogenesis According to the Nrf2-Small Maf Heterodimer 査読有り

    Masanobu Morita, Hozumi Motohashi

    Oxidative Stress in Vertebrates and Invertebrates: Molecular Aspects of Cell Signaling　63-82　2011年11月7日

    出版者・発行元： John Wiley and Sons

    DOI： 10.1002/9781118148143.ch5 　

  46. Kruppel-like factor 5 Is Essential for Blastocyst Development and the Normal Self-Renewal of Mouse ESCs 査読有り

    Masatsugu Ema, Daisuke Mori, Hitoshi Niwa, Yoshikazu Hasegawa, Yojiro Yamanaka, Seiji Hitoshi, Junsei Mimura, Yoh-ichi Kawabe, Tomohiro Hosoya, Masanobu Morita, Daisuke Shimosato, Kazuhiko Uchida, Norio Suzuki, Jun Yanagisawa, Kazuhiro Sogawa, Janet Rossant, Masayuki Yamamoto, Satoru Takahashi, Yoshiaki Fujii-Kuriyama

    CELL STEM CELL　3　(5)　555-567　2008年11月

    DOI： 10.1016/j.stem.2008.09.003 　

    ISSN：1934-5909

  47. Inducibility of cytochrome P450 1A1 and chemical carcinogenesis by benzo[a]pyrene in AhR repressor-deficient mice 査読有り

    Tomonori Hosoya, Nobuhiko Harada, Junsei Mimura, Hozumi Motohashi, Satoru Takahashi, Osamu Nakajima, Masanobu Morita, Shimako Kawauchi, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　365　(3)　562-567　2008年1月

    DOI： 10.1016/j.bbrc.2007.11.016 　

    ISSN：0006-291X

  48. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells 査読有り

    Atsushi Suzuki, Angel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H. Gaget, Concepcion Rodriguez-Esteban, Juan Carlos Izpisua Belmonte

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　103　(27)　10294-10299　2006年7月

    DOI： 10.1073/pnas.0506945103 　

    ISSN：0027-8424

  49. Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification 査読有り

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H. Gage, Concepcín Rodríguez-Esteban, Juan Carlos Izpiśa Belmonte

    Nature Clinical Practice Cardiovascular Medicine　3　(1)　S114-S122　2006年3月

    DOI： 10.1038/ncpcardio0442 　

    ISSN：1743-4297

  50. Functional analysis of basic transcription element binding protein by gene targeting technology. 招待有り 査読有り

    Morita Masanobu, Kobayashi Akira, Yamashita Toshiharu, Shimanuki Tomomasa, Nakajima Osamu, Takahashi Satoru, Ikegami Shiro, Inokuchi Kaoru, Yamashita Keisuke, Yamamoto Masayuki, Fujii-Kuriyama Yoshiaki

    Mol Cell Biol　23　(7)　2489-2500　2003年4月

    DOI： 10.1128/MCB.23.7.2489-2500.2003 　

  51. Defective development of secretory neurones in the hypothalamus of Arnt2-knockout mice

    Tomonori Hosoya, Tomonori Hosoya, Yoshihito Oda, Satoru Takahashi, Masanobu Morita, Shimako Kawauchi, Masatsugu Ema, Masayuki Yamamoto, Masayuki Yamamoto, Masayuki Yamamoto, Yoshiaki Fujii-Kuriyama, Yoshiaki Fujii-Kuriyama, Yoshiaki Fujii-Kuriyama

    Genes to Cells　6　361-374　2001年5月15日

    DOI： 10.1046/j.1365-2443.2001.00421.x 　

    ISSN：1356-9597

  52. A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through the BTB/POZ domain. 国際誌

    A Kobayashi, H Yamagiwa, H Hoshino, A Muto, K Sato, M Morita, N Hayashi, M Yamamoto, K Igarashi

    Molecular and cellular biology　20　(5)　1733-46　2000年3月

    ISSN：0270-7306

    詳細を見る 詳細を閉じる

    Bach2 is a B-cell- and neuron-specific transcription repressor that forms heterodimers with the Maf-related oncoproteins. We show here that Bach2 activates transcription by interacting with its novel partner MAZR. MAZR was isolated by the yeast two-hybrid screen using the BTB/POZ domain of Bach2 as bait. Besides the BTB/POZ domain, MAZR possesses Zn finger motifs that are closely related to those of the Myc-associated Zn finger (MAZ) protein. MAZR mRNA was coexpressed with Bach2 in B cells among hematopoietic cells and in developing mouse limb buds, suggesting a cooperative role for MAZR and Bach2 in these cells. MAZR forms homo- and hetero-oligomers with Bach2 through the BTB domain, which oligomers bind to guanine-rich sequences. Unlike MAZ, MAZR functioned as a strong activator of the c-myc promoter in transfection assays with B cells. However, it does not possess a typical activation domain, suggesting a role for it as an unusual type of transactivator. The fgf4 gene, which regulates morphogenesis of limb buds, contains both guanine-rich sequences and a Bach2 binding site in its regulatory region. In transfection assays using fibroblast cells, the fgf4 gene was upregulated in the presence of both MAZR and Bach2 in a BTB/POZ domain-dependent manner. The results provide a new perspective on the function of BTB/POZ domain factors and indicate that BTB/POZ domain-mediated oligomers of transcription factors may serve as combinatorial codes for gene expression.

  53. Regulation of lens fiber cell differentiation by transcription factor c- Maf

    Shimako Kawauchi, Satoru Takahashi, Osamu Nakajima, Hajime Ogino, Masanobu Morita, Makoto Nishizawa, Kunio Yasuda, Masayuki Yamamoto

    Journal of Biological Chemistry　274　(27)　19254-19260　1999年7月2日

    DOI： 10.1074/jbc.274.27.19254 　

    ISSN：0021-9258

  54. cDNA Cloning of a Murine Homologue ofDrosophilaSingle-Minded, Its mRNA Expression in Mouse Development, and Chromosome Localization

    Masatsugu Ema, Michiko Suzuki, Masanobu Morita, Ken Hirose, Kazuhiro Sogawa, Youich Matsuda, Osamu Gotoh, Yukio Saijoh, Hideta Fujii, Hiroshi Hamada, Yoshiaki Fujii-Kuriyama

    Biochemical and Biophysical Research Communications　218　(2)　588-594　1996年1月

    出版者・発行元： Elsevier BV

    DOI： 10.1006/bbrc.1996.0104 　

    ISSN：0006-291X

  55. Two new members of the murine Sim gene family are transcriptional repressors and show different expression patterns during mouse embryogenesis

    Masatsugu Ema, Masanobu Morita, Shuntaro Ikawa, Masahiro Tanaka, Youichi Matsuda, Osamu Gotoh, Yukio Saijoh, Hideta Fujii, Hiroshi Hamada, Yasuo Kikuchi, Yoshiaki Fujii-Kuriyama

    Molecular and Cellular Biology　16　(10)　5865-5875　1996年

    出版者・発行元： American Society for Microbiology

    DOI： 10.1128/MCB.16.10.5865 　

    ISSN：0270-7306

︎全件表示 ︎最初の5件までを表示

MISC 33

  1. Cyclo-octa-sulfur contributes to energy metabolism in mitochondria

    Tetsuro Matsunaga, Uladzimir Barayeu, Masanobu Morita, Seiryo Ogata, Minkyung Jung, Tianli Zhang, Tsuyoshi Takata, Michito Yoshizawa, Hozumi Motohashi, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　233　2025年6月

    DOI： 10.1016/j.freeradbiomed.2025.05.190 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  2. Physiological formation and function of supersulfides, cyclo-octasulfur (S8) in adipocyte

    Zizai Shen, Minkyung Jung, Uladzimir Barayeu, Tsuyoshi Takata, Tetsuro Matsunaga, Seiryo Ogata, Jun Yoshitake, Masanobu Morita, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　233　2025年6月

    DOI： 10.1016/j.freeradbiomed.2025.05.194 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  3. A novel pathway for supersulfides production catalyzed by NOX and NOS

    Tsuyoshi Takata, Uladzimir Barayeu, Tetsuro Matsunaga, Minkyung Jung, Seiryo Ogata, Masanobu Morita, Yukihiro Tsuchiya, Yasuo Watanabe, Hozumi Motohashi, Michito Yoshizawa, Hideki Sumimoto, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　233　2025年6月

    DOI： 10.1016/j.freeradbiomed.2025.05.191 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  4. Supersulfides protect against SARS-CoV-2 infection by targeting viral thiol proteases and spike proteins

    Seiryo Ogata, Tetsuro Matsunaga, Masanobu Morita, Minkyung Jung, Uladzimir Barayeu, Tsuyoshi Takata, Hozumi Motohashi, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　233　2025年6月

    DOI： 10.1016/j.freeradbiomed.2025.05.080 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  5. Evolutionarily conserved cyclo-octasulfur prevents ferroptosis in mammals

    Uladzimir Barayeu, Seiryo Ogata, Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Mike Lange, Masanobu Morita, Yuka Unno, Saber Boushehri, Tomoaki Ida, Akira Nishimura, Lorenzo Catti, Takayuki Shimizu, Ryo Ushioda, Takakazu Nakabayashi, Seji Asamitsu, Kazuki Fusegawa, Takashi Suzuki, Takanori Ishida, Naoko Tanda, Yasuo Watanabe, Ryo Yamaguchi, Fumiko Yano, Mieko Arisawa, Albert van der Vliet, Dennis Stuehr, Frauke Graeter, Camilo Aponte-Santamaria, James A. Olzmann, Marcus Conrad, Tobias P. Dick, Hozumi Motohashi, Michito Yoshizawa

    FREE RADICAL BIOLOGY AND MEDICINE　233　2025年6月

    DOI： 10.1016/j.freeradbiomed.2025.05.038 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  6. NADPHオキシダーゼおよびNO合成酵素による超硫黄代謝と感染防御機能

    高田剛, 松永哲郎, BARAYEU Uladzimir, 緒方星陵, 守田匡伸, JUNG Minkyung, 土屋幸弘, 渡邊泰男, 本橋ほづみ, 吉沢道人, 住本英樹, 赤池孝章

    日本生体防御学会学術総会講演抄録集　35th (Web)　2024年

  7. 超硫黄分子貯蔵庫としての脂肪細胞の役割

    海野雄加, 松永哲郎, BARAYEU Uladzimir, 緒方星陵, JUNG Minkyung, CATTI Lorenzo, 吉沢道人, 守田匡伸, 高田剛, 赤池孝章

    日本生化学会大会(Web)　97th　2024年

  8. 硫黄転移酵素ロダネーゼによる超硫黄分子の代謝機能の解明

    下澤理, 高田剛, JUNG Minkyung, 海野雄加, 佐藤聡, 守田匡伸, BARAYEU Uladzimir, 松永哲郎, 本橋ほづみ, 赤池孝章

    日本生化学会大会(Web)　97th　2024年

  9. NADPHオキシダーゼおよびNO合成酵素による超硫黄活性化機構の解明

    高田剛, 松永哲郎, 松永哲郎, BARAYEU Uladzimir, 緒方星陵, 守田匡伸, JUNG Minkyung, 土屋幸弘, 渡邊泰男, 本橋ほづみ, 吉沢道人, 住本英樹, 赤池孝章

    日本生化学会大会(Web)　97th　2024年

  10. NADPHオキシダーゼおよび一酸化窒素合成酵素による超硫黄分子活性化と宿主防御機構

    JUNG Minkyung, 高田剛, 井田智章, 松永哲郎, 守田匡伸, 土屋幸弘, 渡邊泰男, 本橋ほづみ, 住本英樹, 赤池孝章

    日本細菌学雑誌(Web)　78　(1)　2023年

    ISSN： 1882-4110

  11. 細菌から動物まで種横断的に保存された超硫黄分子合成経路の発見

    井田智章, JUNG Minkyung, 松永哲郎, 守田匡伸, 緒方星陵, 高田剛, 海野雄加, 本橋ほづみ, 赤池孝章

    日本細菌学雑誌(Web)　78　(1)　2023年

    ISSN： 1882-4110

  12. 新型コロナウイルス感染に関わる呼気・空間オミックス解析

    朝光世志, 緒方星稜, 井田智章, 松永哲郎, JUNG Minkyung, 高田剛, 守田匡伸, 本橋ほづみ, 赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　76th　2023年

  13. 脂肪細胞が担う超硫黄分子貯蔵庫としての役割

    海野雄加, 松永哲郎, 井田智章, ジョン ミンギョン, 高田剛, 守田匡伸, 緒方星陵, 本橋ほづみ, 吉沢道人, 赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　76th　2023年

  14. 超硫黄分子による新型コロナウイルスプロテアーゼ阻害と抗ウイルス効果

    JUNG Minkyung, 松永哲郎, 井田智章, 高田剛, 守田匡伸, 赤池孝章

    日本生体防御学会学術総会講演抄録集　33rd　2022年

  15. 培養脂肪細胞を用いた超硫黄分子S8の代謝機構の解明

    海野雄加, 井田智章, 高田剛, 松永哲郎, 守田匡伸, JUNG Minkyung, 吉沢道人, 赤池孝章

    日本生体防御学会学術総会講演抄録集　33rd　2022年

  16. NADPH酸化還元酵素による超硫黄分子活性化と感染防御

    高田剛, 井田智章, 松永哲郎, 守田匡伸, JUNG Minkyung, 土屋幸弘, 渡邊泰男, 本橋ほづみ, 吉沢道人, 住本英樹, 赤池孝章

    日本生体防御学会学術総会講演抄録集　33rd　2022年

  17. 呼気オミックスによる生体防御応答解析

    井田智章, 高田剛, 松永哲郎, 守田匡伸, JUNG Minkyung, 本橋ほづみ, 赤池孝章

    日本生体防御学会学術総会講演抄録集　33rd　2022年

  18. Aminoacyl-tRNA synthetaseによる超硫黄分子合成機構の解明

    ジョン ミンギョン, 井田智章, 西村明, 松永哲郎, 守田匡伸, 高田剛, 本橋ほづみ, 赤池孝章

    日本生化学会大会(Web)　95th　2022年

  19. T細胞受容体(TCR)/CD3複合体を標的とした超硫黄分子による免疫応答制御

    守田 匡伸, 山田 充啓, 佐々木 優作, 井田 智章, 松永 哲郎, 高田 剛, 渡部 聡, 稲葉 謙次, 石井 直人, 杉浦 久敏, 本橋 ほづみ, 赤池 孝章

    日本生化学会大会プログラム・講演要旨集　94回　[P-890]　2021年11月

    出版者・発行元： (公社)日本生化学会

  20. Chapter 16: Supersulfide-Mediated Signaling during Differentiation and De-Differentiation 招待有り

    Tsuyoshi Takata, Masanobu Morita, Tetsuro Matsunaga, Hozumi Motohashi, Takaaki Akaike

    Redox Regulation of Differentiation and De-Differentiation　271-281　2021年8月26日

    出版者・発行元： CRC Press

    DOI： 10.1201/9781003204091 　

  21. 新興感染症菌Helicobacter cinaediの骨髄内の潜伏感染と細胞内寄生性の分子機構の解明

    松永 哲郎, 西村 明, 守田 匡伸, 井田 智章, 津々木 博康, 澤 智裕, 河村 好章, 赤池 孝章

    日本細菌学雑誌　74　(1)　104-104　2019年3月

    出版者・発行元： 日本細菌学会

    ISSN： 0021-4930

  22. Mitochondria-specific SQR deficiency in mice causes lethal impairment of sulfur respiration

    Masanobu Morita, Tomoaki Ida, Tomohiro Tanaka, Tetsuro Matsunaga, Akira Nishimura, Shigemoto Fujii, Motohiro Nishida, Hozumi Motohashi, Takaaki Akaike

    FREE RADICAL BIOLOGY AND MEDICINE　128　S90-S90　2018年11月

    DOI： 10.1016/j.freeradbiomed.2018.10.209 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  23. 活性イオウ分子種によるミトコンドリア膜電位形成機構の解明

    松永哲郎, 守田匡伸, 西村明, 井田智章, 藤井重元, 本橋ほづみ, 赤池孝章

    日本生化学会大会(Web)　91st　ROMBUNNO.1P‐160 (WEB ONLY)-160]　2018年9月

    出版者・発行元： (公社)日本生化学会

  24. 【レドックス疾患学 酸素・窒素・硫黄活性種はどう作用するのか、どこまで健康・疾患と関わるのか?】 (第3章)レドックスの検出手法、応用など 活性イオウメタボローム イオウ代謝物とレドックスバイオマーカー

    井田 智章, 西村 明, 守田 匡伸

    実験医学　36　(5)　865-873　2018年3月

    出版者・発行元： (株)羊土社

    ISSN： 0288-5514

  25. 新興感染症菌Helicobacter cinaediの骨髄内における潜伏感染と細胞内寄生性の解析

    松永哲郎, 西村明, 守田匡伸, 藤井重元, 井田智章, 澤智裕, 河村好章, 赤池孝章

    日本細菌学雑誌(Web)　73　(1)　117(J‐STAGE)-117　2018年2月

    出版者・発行元： 日本細菌学会

    ISSN： 1882-4110

  26. 新興感染症菌Helicobacter cinaediの骨髄内における潜伏感染と細胞内寄生性の解析

    松永 哲郎, 西村 明, 守田 匡伸, 藤井 重元, 井田 智章, 澤 智裕, 河村 好章, 赤池 孝章

    日本細菌学雑誌　73　(1)　117-117　2018年2月

    出版者・発行元： 日本細菌学会

    ISSN： 0021-4930

  27. ニトロソグルタチオン還元酵素(GSNOR)選択的欠損マウスの開発

    松永 哲郎, 西村 明, 笠松 真吾, Alam Morshedul, 井田 智章, 守田 匡伸, 居原 秀, 藤井 重元, 下田 翔, 西田 基宏, 本橋 ほづみ, 赤池 孝章

    生命科学系学会合同年次大会　2017年度　[3P-0480]　2017年12月

    出版者・発行元： 生命科学系学会合同年次大会運営事務局

  28. 細菌のイオウ呼吸はすべての生物種に保存されている:ほ乳類における新しいエネルギー代謝経路・イオウ呼吸の発見

    赤池孝章, 井田智章, 松永哲郎, 守田匡伸, 笠松真吾, 西村明, 藤井重元, 居原秀, JUNG Minkyung, 赤司壮一郎, 澤智裕, 本橋ほづみ

    日本細菌学雑誌(Web)　72　(1)　98(J‐STAGE)-98　2017年2月

    出版者・発行元： 日本細菌学会

    ISSN： 1882-4110

  29. Protein polysulfidation-dependent persulfide dioxygenase activity of ethylmalonic encephalopathy protein 1 国際誌

    Minkyung Jung, Shingo Kasamatsu, Tetsuro Matsunaga, Soichiro Akashi, Katsuhiko Ono, Akira Nishimura, Masanobu Morita, Hisyam Abdul Hamid, Shigemoto Fujii, Hiroshi Kitamura, Tomohiro Sawa, Tomoaki Ida, Hozumi Motohashi, Takaaki Akaike

    Biochemical and Biophysical Research Communications　480　(2)　180-186　2016年11月11日

    DOI： 10.1016/j.bbrc.2016.10.022 　

    ISSN： 0006-291X

  30. タンパク質ポリサルファ化の分子メカニズムの解明

    井田 智章, 魏 研范, 笠松 真吾, 守田 匡伸, 松永 哲郎, 居原 秀, 富澤 一仁, 熊谷 嘉人, 澤 智裕, 本橋 ほづみ, 赤池 孝章

    日本生化学会大会プログラム・講演要旨集　89回　[1T14-06(1P　2016年9月

    出版者・発行元： (公社)日本生化学会

  31. Generation of Nrf2 point mutant mice by CRISPR/Cas9 system

    Masanobu Morita, Takafumi Suzuki, Hiromi Suda, Akihito Otsuki, Mikiko Suzuki, Ritsuko Shimizu, Masayuki Yamamoto

    TRANSGENIC RESEARCH　23　(5)　874-874　2014年10月

    ISSN： 0962-8819

    eISSN： 1573-9368

  32. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin.

    Morita Masanobu, Ohneda Osamu, Yamashita Toshiharu, Takahashi Satoru, Suzuki Norio, Nakajima Osamu, Kawauchi Shimako, Ema Masatsugu, Shibahara Shigeki, Udono Tetsuo, Tomita Koji, Tamai Makoto, Sogawa Kazuhiro, Yamamoto Masayuki, Fujii-Kuriyama Yoshiaki

    EMBO J　22　(5)　1134-1146　2003年

    DOI： 10.1093/emboj/cdg117 　

  33. Transcription regulation by Ah receptor, Arnt and their related transcription factors

    Y Fujii-Kuriyama, A Kobayashi, M Ema, J Mimura, M Morita, K Sogawa

    FASEB JOURNAL　11　(9)　A780-A780　1997年7月

    ISSN： 0892-6638

︎全件表示 ︎最初の5件までを表示

書籍等出版物 1

  1. Oxidative Stress in Vertebrates and Invertebrates: Molecular Aspects of Cell Signaling

    Tahira Farooqui Akhlaq, A. Farooqui, ed, Masanobu Morita Hozumi Motohashi

    Wiley-Blackwell　2011年10月24日

講演・口頭発表等 2

  1. 前肢・後肢特異的な転写制御の機構

    守田匡伸, Juan Calros, Izpisua Belmonte, 山本雅之

    日本生化学会東北支部第75回例会　2009年5月9日

  2. Fore/hindlimb specific enhancer analysis in diferent tetrapods 国際会議

    守田匡伸

    The 16th CDB meeting cis-sequence redulationn and its evolution　2008年9月29日

共同研究・競争的資金等の研究課題 13

  1. 新規パースルフィド合成酵素の発見と生理機能の解明

    井田 智章, 守田 匡伸

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Osaka Metropolitan University

    2023年4月1日 ～ 2026年3月31日

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    システインパースルフィド(CysSSH)に代表される超硫黄分子は、生体内に豊富に生成され、酸化ストレスに起因する様々な病態・疾患に対して防御的機能を発揮している。研究代表者らは、質量分析装置を用いた硫黄メタボロームを確立して、CysSSH生合成系としてシステインtRNA合成酵素(CARS; 翻訳関連酵素の一つ)を同定し、CARS由来の超硫黄分子がレドックスシグナルやエネルギー代謝などの多彩な生理活性を担っていることを報告してきた。しかしながら、超硫黄分子の生合成系の全貌解明には至っていない。そこで本研究では、全生物種が有するアミノアシルtRNA合成酵素(ARS)が新規パースルフィド合成酵素として機能していることを酵素反応論により検証し、さらに、各種ARS遺伝子改変バイオリソースを用いてエネルギー代謝や寿命等を解析することで、新たなパースルフィド合成反応機構とその生理機能を解明する。 本年度は、まず、CARSによるCysSSH合成活性制御機構を探索するなかで、CysSSH合成活性中心であるPLP結合部位の周辺アミノ酸配列を変異した変異体CARSを合成・精製し、そのCysSSH合成活性を解析した。その結果、PLP結合部位の周辺アミノ酸配列は生物種横断的に高く保存されており、この周辺アミノ酸配列によってCysSSH合成活性が制御されていることを見出した。 次に、大腸菌CARSの酵素反応機構を解析する中で、CARSだけでなく、各種組換えARSを合成・精製し、それらのCysSSH合成活性を検討した結果、ロイシルtRNA合成酵素を筆頭に他の多くのARSにもパースルフィド産生能があることが示された。

  2. 超硫黄分子によるT細胞免疫応答制御

    石井 直人, 守田 匡伸, 河部 剛史, 宗 孝紀

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2023年4月1日 ～ 2026年3月31日

  3. 超硫黄分子の代謝制御メカニズムの解明

    守田 匡伸, 松永 哲郎, 井田 智章

    2023年4月1日 ～ 2026年3月31日

  4. 環境性肺疾患における炭素微粒子受容体の病理的役割

    中山 勝文, 守田 匡伸

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Ritsumeikan University

    2022年4月1日 ～ 2025年3月31日

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    これまでに我々はカーボンナノチューブ（CNT）を認識する免疫受容体としてT cell mucin immunoglobulin (Tim) 4を同定し、Tim4の細胞外芳香族アミノ酸クラスターとCNT表面とのaromatic-aromatic interactionが安定して結合することを明らかにしてきた（Omori et al., Cell Rep., 2021）。しかしながらTim4の発現はヒト末梢血単核球や肺胞マクロファージに発現していないことから、他にもCNT認識受容体が存在する可能性が示唆された。そのため、Tim4の炭素微粒子認識様式に着目し、細胞外芳香族アミノ酸クラスターを持つ受容体をin silico探索した。その結果、Sialic acid-binding immunoglobulin-like lectin (Siglec)5/14を新たなCNT結合受容体として同定することに成功した（Yamaguchi et al., Nat. Nanotechnol., 2023）。興味深いことにSiglec-14はCNTを認識して、Syk経路を介して貪食シグナルと炎症シグナルを伝達することが明らかとなった。この点について我々は、抗Siglec-14阻害抗体あるいはSyk阻害剤のホスタマチニブの投与により、CNT誘発性肺炎を軽減することを明らかにした。この結果は、CNTの炎症毒性発現にSiglec-14が関与することを示唆する。

  5. 環境性肺疾患における炭素微粒子受容体の病理的役割

    中山 勝文, 守田 匡伸

    2022年4月1日 ～ 2025年3月31日

  6. イオウ代謝・呼吸システムの機能解明：ゲノム編集とエネルギー代謝解析

    守田 匡伸

    2019年4月1日 ～ 2023年3月31日

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    ミトコンドリアにおいてシステインから合成される硫黄代謝物（パースルフィドなど）が、アミノアシルtRNA酵素の一つであるCARS2や硫化水素キノン還元酵素（sulfide-quinone reductase, SQR）によって産生・代謝され、エネルギー代謝に関与することが示唆されている(Akaike et al., Nature Commun. 2017)。これは、生物が酸素のみならず硫黄代謝物を利用してエネルギー代謝を営むことを意味している（イオウ代謝・呼吸）。この硫黄代謝の生体内における機能を分子レベルでのメカニズムを明らかにするため、CARS２、SQRの遺伝子改変マウスの作製および解析を行った。CRISPR/Casシステムを用いた精緻なゲノム編集により、パースルフィド活性のみを欠損したパースルフィド不活性化（CARS2点変異）マウス、さらにミトコンドリア移行シグナルを欠損したミトコンドリア選択的SQR欠損マウス（SQR欠損マウス）の作製に成功した。CARS2点変異マウスは胎生致死を示し、SQR欠損マウスは生後3週間以降より成長遅延を示し生後3ヶ月以内に死亡した。解析を進めたところ、これらの遺伝子改変マウスはミトコンドリアにおける硫黄代謝異常を認め、硫黄代謝・呼吸が選択的に抑制された極めてユニークな硫黄代謝不全（エネルギー代謝異常）マウスの開発に成功した。CARS2点変異マウスは胎生致死を示すので、成体での解析が困難であるが、トランスジェニックマウスによるレスキュー法を現在進めており、さらに他の硫黄代謝酵素群であるETHE1、3MST、TSTの遺伝子改変マウスの作製も完了している。これらの遺伝子改変マウスを詳細に解析することで硫黄代謝・呼吸の生体内における機能を明らかにする。

  7. 環境性肺疾患におけるスカベンジャー受容体ファミリーの協調的役割

    中山 勝文, 森本 展行, 守田 匡伸

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Ritsumeikan University

    2019年4月1日 ～ 2022年3月31日

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    環境性肺炎は、大気中汚染物質の曝露により引き起こされる慢性炎症疾患であり、その患者数は年々増加している。その病態には様々な免疫細胞が深く関与していると考えられているが、その病態は複雑であり詳細については未だに多くのことが判っていない。本研究では、PM2.5などの大気中微粒子の主成分の一つであるシリカ（二酸化珪素）による肺炎モデルマウスを用いて、肺胞内免疫細胞上に発現するスカベンジャー受容体（scavenger receptor: SR）ファミリー分子の病理的役割を明らかにした。

  8. 筋内脂肪浸潤と異所性骨化を決定するメカニズムの解明

    谷口 昇, 守田 匡伸, 森永 秀孝, 中島 利博

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Kagoshima University

    2018年4月1日 ～ 2021年3月31日

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    関節の拘縮や機能低下の原因となる筋内脂肪浸潤と異所性骨化の分子メカニズムを解明するため、我々はクロマチン蛋白HMGB2を標的とした研究を行った。Hmgb2-/- MSCを用いて骨分化と脂肪分化誘導を行った結果、野生型と比較して骨分化が促進した一方、脂肪分化は誘導されなかった。脂肪分化においては、HMGB2がそのマスター遺伝子であるPpargとCebpaを介して制御する可能性が示唆された。一方で、マウス骨髄由来間質系細胞であるST-2をBMP-2で骨分化誘導する際、Hmgb2をノックダウンすると、脂肪分化が誘導された。HMGB2は筋内脂肪分化と骨内脂肪分化の両方に関与する可能性がある。

  9. 皮膚組織レベルの紫外線ゲノム毒性防衛応答の制御機構

    池畑 広伸, 鈴木 隆史, 守田 匡伸, 山本 雅之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2015年4月1日 ～ 2018年3月31日

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    紫外線のゲノム毒性に対する皮膚組織レベルの防衛応答である変異誘発抑制（MIS）応答の制御機構を解明するため、抗酸化ストレス応答を制御しているKeap1-Nrf2系が関与するモデルを立て解析を行った。MIS応答のトランスクリプトーム解析を行い、MIS応答に伴うアポトーシス発動遺伝子群の誘導、それに続く組織回復に関係する細胞増殖関連遺伝子群の誘導を認め、アポトーシスとハイパープラシアに基づくMIS応答の機構を確認し、紫外線傷害後の皮膚組織の回復過程におけるKEAP1-NRF2系の関与を認めた。またMIS誘導に必要なDNA損傷量も評価した。

  10. SAM合成酵素を標的とするエピゲノム書き換え法

    加藤 恭丈, 守田 匡伸, 長嶋 剛史, 三枝 大輔, 松本 光代, 五十嵐 和彦

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2013年4月1日 ～ 2016年3月31日

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    メチオニン・アデノシル転移酵素II（MATII）は、S-アデノシルメチオニン（SAM）の生合成を触媒する。合成されたSAMはメチル基転移酵素（MT）の基質として利用され、そのメチル基はDNA中のシトシンやヒストンのリジン残基などへ転移され、クロマチンレベルでのエピジェネティクスを支配する。本研究では、ヒストンやDNAのメチル化を包括的に低下させる方法を開拓し、細胞記憶を消去することである。しかし、当初予定していた細胞記憶の書き替え法にまでは、至っていない。一方、核移行に必要な因子群の同定や、MATIIαが核移行するために必要と示唆される翻訳後修飾の動態から、理解可能となった。

  11. Nrf2誘導剤による肺発生遺伝子群活性化を利用したiPS細胞からの効率的肺再生

    佐藤 大希, 守田 匡伸, 森口 尚

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Young Scientists (B)

    2013年4月1日 ～ 2015年3月31日

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    肺再生分野はその複雑な組織形態のため研究が遅れている分野である。抗酸化ストレス転写因子Nrf2が肺再生遺伝子の活性化に関与しているという知見から、Nr2の存在が肺再生を促進させるかを検討した。マウスの実験からNrf2の存在が肺再生に重要な役割を担っていることが明らかになり、更に詳細なメカニズムを解明するため多能性幹細胞を用いた肺分化誘導実験を行った。今回の結果から、Nrf2が肺再生に関与するという結果が得られたことは、肺再生分野の発展に寄与することが期待される。

  12. 酸化ストレスシグナルによる幹細胞分化促進と脱分化抑制機構の解明

    守田 匡伸

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2012年4月1日 ～ 2015年3月31日

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    酸化ストレスが未分化細胞の増殖や分化の制御にも深く関与していることが近年の研究により明らかになってきた。本研究では酸化―抗酸化のバランス調節において中心的な役割を果たしているKeap1-Nrf2システムがリプログラミング時において重要な役割を担っていることを明らかにした。Nrf2の活性化により細胞周期を停止させる因子が誘導され、iPS形成を抑制していることが明らかになった。

  13. Keap1-Nrf2を介した酸化ストレスシグナルの幹細胞における役割

    守田 匡伸

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Young Scientists (B)

    研究機関：Tohoku University

    2010年 ～ 2011年

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    酸化ストレス応答に関わる遺伝子群Keap1, Nrf2の遺伝子を欠損させたノックアウトES細胞を樹立して、酸化ストレス下での応答性を解析することにより、Keap1-Nrf2を介した酸化ストレスのメカニズムを解明することが本研究の目的である。今年度はKeap1へテロマウス同士の掛け合わせ、およびNrf2へテロ同士の掛け合わせから得られた胚盤胞からES細胞を樹立し、genotypeの判定によりKeap1ノックアウトES、Nrf2ノックアウトES細胞をそれぞれ樹立した。樹立したES細胞は野生型と同様にES細胞様の形状を維持し、幹細胞としての増殖能を保持していた。現在、胚様体形成によるES細胞分化系を行い、これら変異ES細胞の分化能を調べている。

︎全件表示 ︎最初の5件までを表示

その他 1

  1. 肺癌に見られる活性化型Nrf2変異の腫瘍形成における役割

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    肺癌に見られる活性化型Nrf2変異の腫瘍形成における役割