tetano
Editor, Senior Moderator
Elife
. 2024 May 30:12:RP90316.
doi: 10.7554/eLife.90316. Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease
Kejia Zhang[SUP] 1 [/SUP], Patrick Eldin[SUP] 2 [/SUP], Jessica H Ciesla[SUP] 3 [/SUP], Laurence Briant[SUP] 2 [/SUP], Jenna M Lentini[SUP] 1 [/SUP], Jillian Ramos[SUP] 1 [/SUP], Justin Cobb[SUP] 1 [/SUP], Joshua Munger[SUP] 3 [/SUP], Dragony Fu[SUP] 1 [/SUP]
Affiliations
Nonstructural protein 5 (Nsp5) is the main protease of SARS-CoV-2 that cleaves viral polyproteins into individual polypeptides necessary for viral replication. Here, we show that Nsp5 binds and cleaves human tRNA methyltransferase 1 (TRMT1), a host enzyme required for a prevalent post-transcriptional modification in tRNAs. Human cells infected with SARS-CoV-2 exhibit a decrease in TRMT1 protein levels and TRMT1-catalyzed tRNA modifications, consistent with TRMT1 cleavage and inactivation by Nsp5. Nsp5 cleaves TRMT1 at a specific position that matches the consensus sequence of SARS-CoV-2 polyprotein cleavage sites, and a single mutation within the sequence inhibits Nsp5-dependent proteolysis of TRMT1. The TRMT1 cleavage fragments exhibit altered RNA binding activity and are unable to rescue tRNA modification in TRMT1-deficient human cells. Compared to wild-type human cells, TRMT1-deficient human cells infected with SARS-CoV-2 exhibit reduced levels of intracellular viral RNA. These findings provide evidence that Nsp5-dependent cleavage of TRMT1 and perturbation of tRNA modification patterns contribute to the cellular pathogenesis of SARS-CoV-2 infection.
Keywords: Nsp5; SARS-CoV-2; TRMT1; biochemistry; chemical biology; coronavirus; human; infectious disease; main protease; microbiology; tRNA; viruses.
. 2024 May 30:12:RP90316.
doi: 10.7554/eLife.90316. Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease
Kejia Zhang[SUP] 1 [/SUP], Patrick Eldin[SUP] 2 [/SUP], Jessica H Ciesla[SUP] 3 [/SUP], Laurence Briant[SUP] 2 [/SUP], Jenna M Lentini[SUP] 1 [/SUP], Jillian Ramos[SUP] 1 [/SUP], Justin Cobb[SUP] 1 [/SUP], Joshua Munger[SUP] 3 [/SUP], Dragony Fu[SUP] 1 [/SUP]
Affiliations
- PMID: 38814682
- DOI: 10.7554/eLife.90316
Nonstructural protein 5 (Nsp5) is the main protease of SARS-CoV-2 that cleaves viral polyproteins into individual polypeptides necessary for viral replication. Here, we show that Nsp5 binds and cleaves human tRNA methyltransferase 1 (TRMT1), a host enzyme required for a prevalent post-transcriptional modification in tRNAs. Human cells infected with SARS-CoV-2 exhibit a decrease in TRMT1 protein levels and TRMT1-catalyzed tRNA modifications, consistent with TRMT1 cleavage and inactivation by Nsp5. Nsp5 cleaves TRMT1 at a specific position that matches the consensus sequence of SARS-CoV-2 polyprotein cleavage sites, and a single mutation within the sequence inhibits Nsp5-dependent proteolysis of TRMT1. The TRMT1 cleavage fragments exhibit altered RNA binding activity and are unable to rescue tRNA modification in TRMT1-deficient human cells. Compared to wild-type human cells, TRMT1-deficient human cells infected with SARS-CoV-2 exhibit reduced levels of intracellular viral RNA. These findings provide evidence that Nsp5-dependent cleavage of TRMT1 and perturbation of tRNA modification patterns contribute to the cellular pathogenesis of SARS-CoV-2 infection.
Keywords: Nsp5; SARS-CoV-2; TRMT1; biochemistry; chemical biology; coronavirus; human; infectious disease; main protease; microbiology; tRNA; viruses.