{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T20:11:28Z","timestamp":1778875888957,"version":"3.51.4"},"reference-count":97,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["HL152446"],"award-info":[{"award-number":["HL152446"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["5T32AR053461"],"award-info":[{"award-number":["5T32AR053461"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["HL128362"],"award-info":[{"award-number":["HL128362"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["HL146868"],"award-info":[{"award-number":["HL146868"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AR077106"],"award-info":[{"award-number":["R01AR077106"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,23]]},"abstract":"<jats:p>How SARS-CoV-2 causes a wide range of clinical manifestations and disease severity remains poorly understood. SARS-CoV-2 encodes 2 proteases (3CLPro and PLPro), vital for viral production, but also promiscuous with respect to host protein targets. Pharmacological inhibition of 3CLPro markedly reduced hospitalization and death in Phase 2\/3 clinical studies. Here, we develop a bioinformatic algorithm, leveraging experimental data from SARS-CoV, to predict host cleavage targets of 3CLPro. We capture targets of 3CLPro described previously for SARS-CoV-2, as well as thousands of putative targets. We validate numerous targets cleaved during infection, including the giant sarcomeric protein obscurin and the innate immune protein OAS1. A long form of OAS1, p46, has been associated in numerous GWAS studies with lesser COVID disease severity. We show that 3CLPro cleaves p46 OAS1 immediately upstream of a known prenylation domain, relocalizing OAS1 from subcellular membranes to the cytosol, rendering it akin to the nonprotective, cytosolic p42 isoform. Similar OAS1 relocalization occurs upon infection by SARS-CoV-2. Our data provide a high-throughput resource to identify putative host cleavage targets of 3CLPro and reveal a mechanism by which SARS-CoV-2 antagonizes host innate immunity in individuals with the protective p46 isoform of OAS1.<\/jats:p>","DOI":"10.1172\/jci.insight.185739","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:19:42Z","timestamp":1771863582000},"source":"Crossref","is-referenced-by-count":0,"title":["Unbiased cleavage site prediction uncovers viral antagonism of host innate immunity by SARS-CoV-2 3C-like protease"],"prefix":"10.1172","volume":"11","author":[{"given":"Nora","family":"Yucel","sequence":"first","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6198-518X","authenticated-orcid":true,"given":"Silvia","family":"Marchiano","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine,"},{"name":"Center for Cardiovascular Biology, and"},{"name":"Department of Laboratory Medicine & Pathology, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan","family":"Tchelepi","sequence":"additional","affiliation":[{"name":"NetQuest Corporation, Mt. Laurel Township, New Jersey, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Germana","family":"Paterlini","sequence":"additional","affiliation":[{"name":"Certusoft, Bloomington, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan A.","family":"Kuznetsov","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Li","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quentin","family":"McAfee","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nehaar","family":"Nimmagadda","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andy","family":"Ren","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sam","family":"Shi","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyssa","family":"Grogan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-1959","authenticated-orcid":true,"given":"Aikaterini","family":"Kontrogianni-Konstantopoulos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Murry","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine,"},{"name":"Center for Cardiovascular Biology, and"},{"name":"Department of Laboratory Medicine & Pathology, University of Washington, Seattle, Washington, USA."},{"name":"Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA."},{"name":"Sana Biotechnology, Seattle, Washington, USA."},{"name":"Department of Bioengineering, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1368-2453","authenticated-orcid":true,"given":"Zoltan","family":"Arany","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30120-1"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0603-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2002032"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.12839"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2020.09.054"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101019"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.11417"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01136-X"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2286-9"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.12.004"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.12.006"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/6543"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66271"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay2002"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02798-06"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9571"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2019.02.001"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-83-3-595"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.1c00237"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77794-5"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00468-6"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21060-3"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2118542"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26239-2"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2107108118"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2020.1870414"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25796-w"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109892"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2020.104089"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1039\/c2cs15331a"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/v13030369"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02236-09"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-5-72"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013197"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjad024"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.91168.3"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cells13191614"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2022643118"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.virs.2022.04.006"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01373-23"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00037-22"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.virs.2025.07.002"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3405"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf7872"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.02.008"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001558"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2007.02.015"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv332"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2019.08.002"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1668"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1021\/bi00699a001"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2021.01.002"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0088162"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.3A6183.2004"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00497.2003"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-5761com"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2018.tb00019.x"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03767-x"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2020283"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-022-01089-8"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.859387"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.777076"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042718-041356"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2007.02.003"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00996-8"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01281-1"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1086\/429391"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj3624"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71047"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-15-33"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1890"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2020.05.009"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/nri2314"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00319-19"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.04.011"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1306917110"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-018-2191-3"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003401"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138568"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2020.09.060"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13532"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.3538"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_202005_21217"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0282151"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.049465"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa664"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-021-00790-1"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2022.12.004"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2204919"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00507-2"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac673"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac443"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(25)00073-8"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2024.2007"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1038\/s43856-024-00668-8"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-46912-4"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/185739\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:32:35Z","timestamp":1778873555000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/185739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":97,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2,23]]},"published-print":{"date-parts":[[2026,2,23]]}},"alternative-id":["10.1172\/jci.insight.185739"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.185739","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]},"article-number":"e185739"}}