{"doi":"10.1073/pnas.2419620122","title":"Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways","abstract":"Identifying conserved mechanisms used by viruses to delay host innate responses can reveal potential targets for antiviral therapeutics. Here, we investigated coronavirus nonstructural protein 15 (nsp15), which encodes a highly conserved endoribonuclease (EndoU). EndoU functions as an immune antagonist by limiting the accumulation of viral replication intermediates that would otherwise be sensed by the host. Despite being a promising antiviral target, it has been difficult to develop small-molecule inhibitors that target the EndoU active site. We generated nsp15 mutants of the coronaviruses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mouse hepatitis virus (MHV)-A59 and identified conserved residues within the amino-terminal domain that are required for EndoU activity. Loss of EndoU activity caused the activation of host sensors, which limited viral replication in interferon-responsive cells and attenuated disease in MHV-infected mice. Using transcriptional profiling, we found that MHV EndoU mutant viruses upregulate multiple host sensors, including Z-form nucleic acid-binding protein 1 (ZBP1). We found that nsp15 mutants induced early, robust ZBP1-mediated necroptosis. EndoU mutant viruses also induced ZBP1-independent apoptosis and pyroptosis pathways, causing early, robust cell death that limits virus replication and pathogenesis. Overall, we document the importance of the amino-terminal domain for EndoU function. We also highlight the importance of nsp15/EndoU activity for evading host sensors, delaying cell death, and promoting pathogenesis.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":517142,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":939972,"name":"Shuchen Feng","orcid":"0000-0002-8878-8036","position":1,"is_corresponding":false},{"id":288695,"name":"Allen Caobi","orcid":"0000-0002-2033-0950","position":2,"is_corresponding":false},{"id":805286,"name":"Fernando R. Moreira","orcid":"0000-0002-6606-7668","position":3,"is_corresponding":false},{"id":563015,"name":"Dakota L. Jones","orcid":"0000-0002-3944-5686","position":4,"is_corresponding":false},{"id":234394,"name":"Konstantinos-Dionysios Alysandratos","orcid":null,"position":5,"is_corresponding":false},{"id":377904,"name":"Ena S. Tully","orcid":null,"position":6,"is_corresponding":false},{"id":228731,"name":"Darrell N. Kotton","orcid":"0000-0002-9604-8476","position":7,"is_corresponding":false},{"id":225723,"name":"David F. Boyd","orcid":"0000-0003-1383-4939","position":8,"is_corresponding":false},{"id":606885,"name":"Bridget S. Banach","orcid":"0000-0002-0868-692X","position":9,"is_corresponding":false},{"id":558658,"name":"Robert N. Kirchdoerfer","orcid":"0000-0002-5974-2709","position":10,"is_corresponding":false},{"id":232300,"name":"Mohsan Saeed","orcid":"0000-0001-8505-7054","position":11,"is_corresponding":false},{"id":77531,"name":"Susan C. Baker","orcid":"0000-0001-6485-8143","position":12,"is_corresponding":false},{"id":722679,"name":"Monika Evdokimova","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:48:54.768083Z","pmid":"40035769","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":[]}