Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease
The SARS-CoV-2 main protease (Mpro 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...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/91168 |
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| author | Angel D'Oliviera Xuhang Dai Saba Mottaghinia Sophie Olson Evan P Geissler Lucie Etienne Yingkai Zhang Jeffrey S Mugridge |
| author_facet | Angel D'Oliviera Xuhang Dai Saba Mottaghinia Sophie Olson Evan P Geissler Lucie Etienne Yingkai Zhang Jeffrey S Mugridge |
| author_sort | Angel D'Oliviera |
| collection | DOAJ |
| description | The SARS-CoV-2 main protease (Mpro 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 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that Mpro 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 Mpro-TRMT1 peptide complex that shows how TRMT1 engages the Mpro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 Mpro 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. |
| format | Article |
| id | doaj-art-36c0c446888e4117b2ca3e7a3ca1a2bf |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-36c0c446888e4117b2ca3e7a3ca1a2bf2025-01-07T16:03:55ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011210.7554/eLife.91168Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main proteaseAngel D'Oliviera0https://orcid.org/0000-0002-5944-9609Xuhang Dai1https://orcid.org/0009-0007-6712-8737Saba Mottaghinia2https://orcid.org/0000-0002-9409-3302Sophie Olson3Evan P Geissler4Lucie Etienne5https://orcid.org/0000-0002-8585-7534Yingkai Zhang6https://orcid.org/0000-0002-4984-3354Jeffrey S Mugridge7https://orcid.org/0000-0002-1553-3008Department of Chemistry & Biochemistry, University of Delaware, Newark, United StatesDepartment of Chemistry, New York University, New York, United StatesCIRI (Centre International de Recherche en Infectiologie), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, FranceDepartment of Chemistry & Biochemistry, University of Delaware, Newark, United StatesDepartment of Chemistry & Biochemistry, University of Delaware, Newark, United StatesCIRI (Centre International de Recherche en Infectiologie), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, FranceDepartment of Chemistry, New York University, New York, United States; Simons Center for Computational Physical Chemistry at New York University, New York, United StatesDepartment of Chemistry & Biochemistry, University of Delaware, Newark, United StatesThe SARS-CoV-2 main protease (Mpro 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 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that Mpro 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 Mpro-TRMT1 peptide complex that shows how TRMT1 engages the Mpro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 Mpro 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.https://elifesciences.org/articles/91168host-virus interactionsRNA-protein interactionstRNA modificationsprotease |
| spellingShingle | Angel D'Oliviera Xuhang Dai Saba Mottaghinia Sophie Olson Evan P Geissler Lucie Etienne Yingkai Zhang Jeffrey S Mugridge Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease eLife host-virus interactions RNA-protein interactions tRNA modifications protease |
| title | Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease |
| title_full | Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease |
| title_fullStr | Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease |
| title_full_unstemmed | Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease |
| title_short | Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease |
| title_sort | recognition and cleavage of human trna methyltransferase trmt1 by the sars cov 2 main protease |
| topic | host-virus interactions RNA-protein interactions tRNA modifications protease |
| url | https://elifesciences.org/articles/91168 |
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