biostudies-literatureUnknownD'Oliviera ANIGMS NIH HHSNIH HHSThe SARS-CoV-2 main protease (M^pro, or Nsp5) is critical for the production of functional viral proteins during infection and, like many viral proteases, can also target host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 M^pro. TRMT1 installs the <i>N</i> ²,<i>N</i> ²-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes global protein synthesis and cellular redox homeostasis. We find that M^pro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. TRMT1 proteolysis results in elimination of TRMT1 tRNA methyltransferase activity and reduced tRNA binding affinity. EvolubioRxiv : the preprint server for biology2023.02.20.529306https://www.ebi.ac.uk/biostudies/studies/S-EPMC9980103biostudies-literatureRecognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease.PMC9980103P20 GM104316T32 GM133395P30 GM133893R35 GM127040R35 GM143000S10 OD026896D'Oliviera AMottaghinia SEtienne LGeissler EPZhang YOlson SMugridge JSDai XfalseRecognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease.The SARS-CoV-2 main protease (M^pro, or Nsp5) is critical for the production of functional viral proteins during infection and, like many viral proteases, can also target host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 M^pro. TRMT1 installs the <i>N</i> ²,<i>N</i> ²-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes global protein synthesis and cellular redox homeostasis. We find that M^pro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. TRMT1 proteolysis results in elimination of TRMT1 tRNA methyltransferase activity and reduced tRNA binding affinity. Evolu2024-01-01T00:00:00Z2024 Oct2026-07-06T03:14:46.745Z2025-02-18T22:34:34.587ZS-EPMC99801033686525310.1101/2023.02.20.529306