Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion

Nucleic Acids Res. 2017 Jan 9;45(1):435-445. doi: 10.1093/nar/gkw745. Epub 2016 Aug 27.


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 ms2 modification remains largely unknown. Here, we report that cysteine hydropersulfide (CysSSH), a newly identified reactive sulfur species, is involved in ms2 modification in cells. The suppression of intracellular CysSSH production rapidly reduced ms2 modification, 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 ms2 modification. 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 ms2 modification, and that it contributes to insulin secretion.

MeSH terms

  • Animals
  • Cell Line
  • Cysteine / analogs & derivatives*
  • Cysteine / metabolism
  • Disulfides / metabolism*
  • Free Radicals
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Isotope Labeling
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nucleic Acid Conformation
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism*
  • Sulfhydryl Compounds / metabolism
  • Sulfur / metabolism*
  • tRNA Methyltransferases / genetics
  • tRNA Methyltransferases / metabolism*


  • Disulfides
  • Free Radicals
  • Insulin
  • Nerve Tissue Proteins
  • Sulfhydryl Compounds
  • cysteine persulfide
  • Sulfur
  • RNA, Transfer
  • tRNA Methyltransferases
  • CDKAL1 protein, human
  • CDKAL1 protein, mouse
  • Cysteine