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PreprintCited by 3RNA 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

Open access
Zhang, Kejia, Eldin, Patrick, Ciesla, Jessica H., Briant, Laurence, Lentini, Jenna M., Ramos, Jillian, Cobb, Justin, Munger, Joshua, Fu, Dragony·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.02.10.527147PMC PMC10370084

Preprint — published as 10.7554/elife.90316 · Paper page

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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 wildtype 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)
Corresponding author
Fu, Dragony
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-02-13
DOI
10.1101/2023.02.10.527147
PMC
PMC10370084
OpenAlex
W4320482790
Cited by
3
References
3
Citations by year
2025: 1 · 2023: 2
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion, other-oa)
Funders
  • National Science Foundation (2033354)
  • University of Rochester
  • Agence Nationale de la Recherche (ANR-16-IDEX-0006)
  • Centre Hospitalier Régional Universitaire de Montpellier
  • Montpellier Université d'Excellence (ANR-16IDEX-0006)
  • National Institutes of Health (NIH T32, AI1049815, AI127370)
  • National Institute of General Medical Sciences (T32GM068411)
  • National Institute of Allergy and Infectious Diseases (R01AI150698, R01AI050698, R01AI127370)
  • National Institute of Environmental Health Sciences (P30ES001247)
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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