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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,11]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1073\/pnas.2419620122","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T10:51:56Z","timestamp":1741085516000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways"],"prefix":"10.1073","volume":"122","author":[{"given":"Monika","family":"Evdokimova","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago","place":["Maywood"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchen","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University 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