title: Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion.
abstract: The 2-methylthio (ms2) modification at A37 of tRNAs is critical for accurate decoding, and contributes to metabolic homeostasis in mammals. However, the regulatory mechanism of ms2modification remains largely unknown. Here, we report that cysteine hydropersulfide (CysSSH), a newly identified reactive sulfur species, is involved in ms2modification in cells. The suppression of intracellular CysSSH production rapidly reduced ms2modification, which was rescued by the application of an exogenous CysSSH donor. Using a unique and stable isotope-labeled CysSSH donor, we show that CysSSH was capable of specifically transferring its reactive sulfur atom to the cysteine residues of ms2-modifying enzymes as well as ms2modification. Furthermore, the suppression of CysSSH production impaired insulin secretion and caused glucose intolerance in both a pancreatic β-cell line and mouse model. These results demonstrate that intracellular CysSSH is a novel sulfur source for ms2modification, and that it contributes to insulin secretion.
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Nozomu
authors: N
authors: Takahashi
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors: Fan-Yan
authors: FY
authors: Wei
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Sayaka
authors: S
authors: Watanabe
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Mayumi
authors: M
authors: Hirayama
authors: Dojindo Laboratories, 2025-5 Tabaru Kamimashikigun, Mashikimachi, Kumamoto 861-2202, Japan.
authors: Yuya
authors: Y
authors: Ohuchi
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Atsushi
authors: A
authors: Fujimura
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Taku
authors: T
authors: Kaitsuka
authors: Department of Health Chemistry, Showa Pharmaceutical University, Tokyo 194-8543, Japan.
authors: Isao
authors: I
authors: Ishii
authors: Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556,Japan.
authors: Tomohiro
authors: T
authors: Sawa
authors: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Hideki
authors: H
authors: Nakayama
authors: Department of Environmental Health Sciences and Molecular Toxicology,Tohoku University Graduate School of Medicine, Sendai 980-8577, Japan.
authors: Takaaki
authors: T
authors: Akaike
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan tomikt@kumamoto-u.ac.jp.
authors: Kazuhito
authors: K
authors: Tomizawa
mesh_terms: D000818:Animals; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism*; D005609:Free Radicals; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007553:Isotope Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism*; D012359:tRNA Methyltransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004220:Disulfides; D005609:Free Radicals; D007328:Insulin; D009419:Nerve Tissue Proteins; D013438:Sulfhydryl Compounds; C116840:cysteine persulfide; D013455:Sulfur; D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C525110:CDKAL1 protein, human; C559068:CDKAL1 protein, mouse; D003545:Cysteine