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Cited by 9RNA modifications and cancerRNA and protein synthesis mechanismsSARS-CoV-2 and COVID-19 Research

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Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease

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Zhang, Kejia, Eldin, Patrick, Ciesla, Jessica H, Briant, Laurence, Lentini, Jenna M, Ramos, Jillian, Cobb, Justin, Munger, Joshua, Fu, Dragony·2024·eLife
DOI 10.7554/elife.90316.3

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Abstract

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.

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Metadata

Authors
Zhang, K., Eldin, P., Ciesla, J. H., Briant, L., Lentini, J. M., Ramos, J., Cobb, J., Munger, J., & Fu, D.
Affiliations
  • University of Rochester (US)
  • Centre National de la Recherche Scientifique (FR)
  • University of Rochester Medicine (US)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-05-30
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.90316.3
OpenAlex
W4399172792
Cited by
9
References
3
Citations by year
2026: 3 · 2025: 5 · 2024: 1
FWCI
1.23
Type
journal article
Language
en
Open access
Licence
Locations
eLife (publishedVersion, cc-by)
Funders
  • National Science Foundation (2033354)
  • National Institutes of Health (GM143145, GM068411, AI1049815, AI127370, AI50698)
  • Montpellier Université d'Excellence (CoVIMOD FRS13)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
tRNA methyltransferase, SARS-CoV-2, NSP5, main protease, proteolytic cleavage, host-virus interaction, tRNA modification, post-transcriptional modification, RNA-binding activity, viral RNA levels, COVID-19 pathogenesis

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