Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion

The 2-methylthio (ms(2)) modification at A37 of tRNAs is critical for accurate decoding, and contributes to metabolic homeostasis in mammals. However, the regulatory mechanism of ms(2) modification remains largely unknown. Here, we report that cysteine hydropersulfide (CysSSH), a newly identified reactive sulfur species, is involved in ms(2) modification in cells. The suppression of intracellular CysSSH production rapidly reduced ms(2) 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 ms(2)-modifying enzymes as well as ms(2) 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 ms(2) modification, and that it contributes to insulin secretion.