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Cited by 2RNA modifications and cancerSARS-CoV-2 and COVID-19 ResearchRNA and protein synthesis mechanisms

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Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease

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D'Oliviera, Angel, Dai, Xuhang, Mottaghinia, Saba, Olson, Sophie, Geissler, Evan P, Etienne, Lucie, Zhang, Yingkai, Mugridge, Jeffrey S·2025·eLife
DOI 10.7554/elife.91168PMC PMC11706605

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Abstract

The SARS-CoV-2 main protease (M pro or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 M pro . TRMT1 installs the N 2 , N 2 -dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that M pro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. Evolutionary analysis shows the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. TRMT1 proteolysis results in reduced tRNA binding and elimination of tRNA methyltransferase activity. We also determined the structure of an M pro -TRMT1 peptide complex that shows how TRMT1 engages the M pro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of M pro -mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 M pro that could help guide future antiviral therapeutic development and show how proteolysis of TRMT1 during SARS-CoV-2 infection impairs both TRMT1 tRNA binding and tRNA modification activity to disrupt host translation and potentially impact COVID-19 pathogenesis or phenotypes.

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Metadata

Authors
D'Oliviera, A., Dai, X., Mottaghinia, S., Olson, S., Geissler, E. P., Etienne, L., Zhang, Y., & Mugridge, J. S.
Affiliations
  • Department of Chemistry & Biochemistry, University of Delaware
  • New York University (US)
  • Lyon 1 Université (FR)
  • University of Delaware (US)
Corresponding author
Mugridge, Jeffrey S
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-01-07
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.91168
PMC
PMC11706605
OpenAlex
W4388696603
Cited by
2
References
94
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R35 GM143000, R35 GM127040, T32 GM133395, P20 GM104316, S10 OD026896A)
  • Agence Nationale de la Recherche (ANR-20-CE15-0020-01)
  • French Research Agency on HIV and Emerging Infectious Diseases ANRS/MIE (ECTZ118944)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
main protease, NSP5, tRNA methyltransferase, substrate recognition, proteolysis, zinc finger, Muroidea, host-virus interaction, antiviral agents
MeSH terms
COVID-19, SARS-CoV-2, Coronavirus 3C Proteases, Humans, Protein Binding, RNA, Transfer, tRNA Methyltransferases, HEK293 Cells, Proteolysis

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