{"doi":"10.7554/elife.90316","title":"Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease","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.","journal":"eLife","year":2023,"id":347044,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1087949,"name":"Patrick Eldin","orcid":"0000-0002-3678-1043","position":1,"is_corresponding":false},{"id":554523,"name":"Jessica H. Ciesla","orcid":"0000-0001-5305-5783","position":2,"is_corresponding":false},{"id":1087950,"name":"Laurence Briant","orcid":"0000-0002-1995-3501","position":3,"is_corresponding":false},{"id":298837,"name":"Jenna M. Lentini","orcid":"0000-0002-4069-4102","position":4,"is_corresponding":false},{"id":1088465,"name":"Jillian Ramos","orcid":null,"position":5,"is_corresponding":false},{"id":579595,"name":"Justin Cobb","orcid":"0000-0001-7095-6284","position":6,"is_corresponding":false},{"id":494385,"name":"Joshua Munger","orcid":"0000-0001-5379-9440","position":7,"is_corresponding":false},{"id":298839,"name":"Dragony Fu","orcid":"0000-0002-8725-8658","position":8,"is_corresponding":false},{"id":352772,"name":"Kejia Zhang","orcid":"0000-0002-1089-6782","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:11:53.085356Z","pmid":"38814682","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}