{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T20:24:06Z","timestamp":1794083046431,"version":"4.8.0"},"reference-count":79,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"crossref","award":["1R01AI151006"],"award-info":[{"award-number":["1R01AI151006"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"crossref","award":["1R01AI180125"],"award-info":[{"award-number":["1R01AI180125"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"crossref","award":["1R01AI187352"],"award-info":[{"award-number":["1R01AI187352"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"crossref","award":["75N93022C00035"],"award-info":[{"award-number":["75N93022C00035"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tick-borne negative-sense single-stranded RNA nairoviruses represent a significant global public-health threat. Over the past decade, discoveries of new orthonairoviruses and norwaviruses have surged. Many of these have been observed to cause febrile illness in humans or have been found in vectors that carry other human diseases. All orthonairoviruses encode a viral homologue of the ovarian tumor protease (OTU) superfamily, which is part of the l-protein, and the OTU is conserved in the Norwavirus genus. OTUs exhibit varying levels of deubiquitinating (DUB) and deISGylating activities that facilitate viral immune evasion, establishing them as key virulence factors. Here, these activities from emerging Songling, Yezo, Tacheng tick virus 1, and Pacific Coast Tick orthonairoviruses, as well as the Beiji norwavirus, were investigated. This analysis reveals a diverse range of DUB and human deISGylase enzymatic activities in the previously uncharacterized viral groups. This includes unexpected OTU human deISGylating activity and suggests that OTUs possess functions beyond their established DUB and deISGylating roles. Additionally, the molecular basis of these activities, or the absence thereof, is explored through X-ray crystallographic structures of viral OTUs encoded by four orthonairoviruses and one norwavirus. The biochemical and structural insights provide a path forward for predicting OTU activity among current and emerging nairoviruses.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00320","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:01:02Z","timestamp":1783947662000},"page":"3127-3143","source":"Crossref","is-referenced-by-count":1,"title":["Insights into\nthe Structure and Function of the OTU\nProtease Virulence Factors from Emerging Human Nairoviruses"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0131-7360","authenticated-orcid":true,"given":"David S.","family":"Gonzalez","sequence":"first","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amritpal","family":"Jalf","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Moresco","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Garcia","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Jaroszewski","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Matta","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Torres","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E\u0301ric","family":"Bergeron","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention , , , ,","place":["Atlanta, Georgia, United States, 30329"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Godzik","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2958-5319","authenticated-orcid":true,"given":"Scott D.","family":"Pegan","sequence":"additional","affiliation":[{"name":"University of California Riverside , , , ,","place":["Riverside, California, United States, 92521"]},{"name":"United States Military Academy , , , ,","place":["West Point, New York, United States, 10996"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"issue":"1","key":"2026091109075484000_cit1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007515","article-title":"Probing the impact of nairovirus\ngenomic diversity on viral ovarian tumor domain protease (vOTU) structure\nand deubiquitinase activity","volume":"15","author":"Dzimianski","year":"2019","journal-title":"PLoS Pathog."},{"issue":"8","key":"2026091109075484000_cit2","doi-asserted-by":"publisher","first-page":"001864","DOI":"10.1099\/jgv.0.001864","article-title":"Annual (2023) taxonomic\nupdate of RNA-directed RNA polymerase-encoding negative-sense RNA\nviruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota)","volume":"104","author":"Kuhn","year":"2023","journal-title":"J. Gen. Virol."},{"issue":"4","key":"2026091109075484000_cit3","doi-asserted-by":"publisher","first-page":"001974","DOI":"10.1099\/jgv.0.001974","article-title":"ICTV Virus Taxonomy\nProfile: Nairoviridae 2024","volume":"105","author":"Kuhn","year":"2024","journal-title":"J. Gen. Virol."},{"issue":"7","key":"2026091109075484000_cit4","doi-asserted-by":"publisher","first-page":"3815","DOI":"10.1128\/JVI.03252-12","article-title":"Diversity\nof ubiquitin and ISG15 specificity among nairoviruses\u2019 viral\novarian tumor domain proteases","volume":"87","author":"Capodagli","year":"2013","journal-title":"J. Virol."},{"issue":"7","key":"2026091109075484000_cit5","doi-asserted-by":"publisher","first-page":"3621","DOI":"10.1128\/JVI.02496-10","article-title":"Structural analysis of a viral ovarian tumor domain\nprotease from the Crimean-Congo hemorrhagic fever virus in complex\nwith covalently bonded ubiquitin","volume":"85","author":"Capodagli","year":"2011","journal-title":"J. Virol."},{"issue":"2","key":"2026091109075484000_cit6","doi-asserted-by":"publisher","first-page":"147","DOI":"10.3201\/eid1502.080851","article-title":"Kupe virus, a new virus in the family\nbunyaviridae, genus nairovirus, kenya","volume":"15","author":"Crabtree","year":"2009","journal-title":"Emerg.\nInfect. Dis."},{"issue":"3","key":"2026091109075484000_cit7","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1007\/s11262-012-0796-8","article-title":"Genetic characterization of Erve virus, a European\nNairovirus distantly related to Crimean-Congo hemorrhagic fever virus","volume":"45","author":"Dilcher","year":"2012","journal-title":"Virus Genes"},{"issue":"6","key":"2026091109075484000_cit8","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.chom.2007.09.014","article-title":"Ovarian tumor domain-containing viral proteases evade\nubiquitin- and ISG15-dependent innate immune responses","volume":"2","author":"Frias-Staheli","year":"2007","journal-title":"Cell Host Microbe."},{"issue":"1","key":"2026091109075484000_cit9","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1099\/vir.0.015701-0","article-title":"Differential\nactivation\nprofiles of Crimean-Congo hemorrhagic fever virus- and Dugbe virus-infected\nantigen-presenting cells","volume":"91","author":"Peyrefitte","year":"2010","journal-title":"J. Gen. Virol."},{"key":"2026091109075484000_cit10","first-page":"95","article-title":"Nairobi\nsheep disease","volume":"39","author":"Davies","year":"1988","journal-title":"Parassitologia"},{"issue":"1","key":"2026091109075484000_cit11","first-page":"89","article-title":"Outbreak\nof arbovirus infection in the Tadzhik SSR due to the Issyk-Kul virus\n(Issyk-Kul fever)","volume":"29","author":"L\u2019Vov","year":"1984","journal-title":"Vopr Virusol."},{"issue":"3","key":"2026091109075484000_cit12","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1017\/S0950268800052687","article-title":"Investigation of tick-borne viruses\nas pathogens of\nhumans in South Africa and evidence of Dugbe virus infection in a\npatient with prolonged thrombocytopenia","volume":"116","author":"Burt","year":"1996","journal-title":"Epidemiol.\nInfect."},{"issue":"1","key":"2026091109075484000_cit13","doi-asserted-by":"publisher","first-page":"2502003","DOI":"10.1080\/22221751.2025.2502003","article-title":"Genetic diversity and\nexpanded epidemic area of novel tick-borne pathogen wetland virus\nin ticks, wild and domestic animals, and patient in China","volume":"14","author":"Yuan","year":"2025","journal-title":"Emerg Microbes Infect."},{"issue":"12","key":"2026091109075484000_cit14","doi-asserted-by":"publisher","first-page":"2944","DOI":"10.3201\/eid2612.202411","article-title":"Human-Pathogenic Kasokero Virus in\nField-Collected\nTicks","volume":"26","author":"Schuh","year":"2020","journal-title":"Emerg. Infect. Dis."},{"issue":"1","key":"2026091109075484000_cit15","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1080\/22221751.2021.1936197","article-title":"A new nairo-like virus\nassociated with human febrile illness in China","volume":"10","author":"Wang","year":"2021","journal-title":"Emerg Microbes Infect."},{"issue":"3","key":"2026091109075484000_cit16","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41591-020-01228-y","article-title":"Identification of a\nnew orthonairovirus associated with human febrile illness in China","volume":"27","author":"Ma","year":"2021","journal-title":"Nat. Med."},{"issue":"10","key":"2026091109075484000_cit17","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1093\/cid\/ciz602","article-title":"A Tentative Tamdy Orthonairovirus\nRelated to Febrile Illness in Northwestern China","volume":"70","author":"Liu","year":"2020","journal-title":"Clin. Infect. Dis."},{"issue":"1","key":"2026091109075484000_cit18","doi-asserted-by":"publisher","first-page":"12234","DOI":"10.1038\/s41598-017-12047-6","article-title":"Metagenomic-based\nSurveillance of Pacific Coast tick\nDermacentor occidentalis Identifies Two Novel Bunyaviruses and an\nEmerging Human Ricksettsial Pathogen","volume":"7","author":"Bouquet","year":"2017","journal-title":"Sci. Rep."},{"issue":"1","key":"2026091109075484000_cit19","doi-asserted-by":"publisher","first-page":"5539","DOI":"10.1038\/s41467-021-25857-0","article-title":"A novel nairovirus\nassociated with acute febrile illness\nin Hokkaido, Japan","volume":"12","author":"Kodama","year":"2021","journal-title":"Nat. Commun."},{"issue":"4","key":"2026091109075484000_cit20","doi-asserted-by":"publisher","first-page":"797","DOI":"10.3201\/eid2904.220885","article-title":"Yezo Virus\nInfection in Tick-Bitten Patient and Ticks, Northeastern China","volume":"29","author":"Lv","year":"2023","journal-title":"Emerg. Infect. Dis."},{"issue":"4","key":"2026091109075484000_cit21","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3390\/v8040106","article-title":"Molecular\nInsights into Crimean-Congo Hemorrhagic Fever Virus","volume":"8","author":"Zivcec","year":"2016","journal-title":"Viruses"},{"issue":"1","key":"2026091109075484000_cit22","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1128\/JVI.01859-09","article-title":"Crimean-Congo hemorrhagic\nfever virus-encoded ovarian tumor protease activity is dispensable\nfor virus RNA polymerase function","volume":"84","author":"Bergeron","year":"2010","journal-title":"J. Virol."},{"issue":"10","key":"2026091109075484000_cit23","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.1016\/j.celrep.2017.08.040","article-title":"Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate\nImmune Responses via a Ubiquitin and ISG15 Specific Protease","volume":"20","author":"Scholte","year":"2017","journal-title":"Cell Rep."},{"key":"2026091109075484000_cit24","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The ubiquitin code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu. Rev. Biochem."},{"issue":"Pt 11","key":"2026091109075484000_cit25","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1107\/S2059798320012875","article-title":"Flipping\nthe substrate preference of Hazara virus ovarian tumour domain protease\nthrough structure-based mutagenesis","volume":"76","author":"Dzimianski","year":"2020","journal-title":"Acta Crystallogr.\nD Struct Biol."},{"key":"2026091109075484000_cit26","doi-asserted-by":"publisher","first-page":"11496","DOI":"10.1038\/ncomms11496","article-title":"ISG15 deficiency and increased viral\nresistance in humans but not mice","volume":"7","author":"Speer","year":"2016","journal-title":"Nat. Commun."},{"issue":"18","key":"2026091109075484000_cit27","doi-asserted-by":"publisher","first-page":"8314","DOI":"10.1128\/JVI.00975-16","article-title":"Biochemical and\nStructural Insights into the Preference of Nairoviral DeISGylases\nfor Interferon-Stimulated Gene Product 15 Originating from Certain\nSpecies","volume":"90","author":"Deaton","year":"2016","journal-title":"J. Virol."},{"issue":"12","key":"2026091109075484000_cit28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0226415","article-title":"Determining the\nmolecular drivers of species-specific interferon-stimulated gene product\n15 interactions with nairovirus ovarian tumor domain proteases","volume":"14","author":"Dzimianski","year":"2019","journal-title":"PLoS One"},{"issue":"Pt 1","key":"2026091109075484000_cit29","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1107\/S2059798318015322","article-title":"Structure of interferon-stimulated\ngene product 15\n(ISG15) from the bat species Myotis davidii and the impact of interdomain\nISG15 interactions on viral protein engagement","volume":"75","author":"Langley","year":"2019","journal-title":"Acta Crystallogr. D Struct Biol."},{"issue":"11","key":"2026091109075484000_cit30","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1016\/j.jmb.2017.04.011","article-title":"Structural Insights into the Interaction\nof Coronavirus\nPapain-Like Proteases and Interferon-Stimulated Gene Product 15 from\nDifferent Species","volume":"429","author":"Daczkowski","year":"2017","journal-title":"J. Mol. Biol."},{"issue":"4","key":"2026091109075484000_cit31","doi-asserted-by":"publisher","first-page":"01065","DOI":"10.1128\/mBio.01065-19","article-title":"Stable Occupancy of\nthe Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks\nViral Infection","volume":"10","author":"Scholte","year":"2019","journal-title":"mBio"},{"issue":"5\u20136","key":"2026091109075484000_cit32","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.cytogfr.2008.11.001","article-title":"Interferon and cytokine\nresponses to Crimean Congo\nhemorrhagic fever virus; an emerging and neglected viral zonoosis","volume":"19","author":"Weber","year":"2008","journal-title":"Cytokine Growth Factor Rev."},{"issue":"29","key":"2026091109075484000_cit33","doi-asserted-by":"publisher","first-page":"10200","DOI":"10.1073\/pnas.0504754102","article-title":"Human ISG15\nconjugation targets both IFN-induced and constitutively expressed\nproteins functioning in diverse cellular pathways","volume":"102","author":"Zhao","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"5","key":"2026091109075484000_cit34","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1073\/pnas.1412881112","article-title":"Selective\ninactivation of USP18 isopeptidase activity\nin vivo enhances ISG15 conjugation and viral resistance","volume":"112","author":"Ketscher","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"4","key":"2026091109075484000_cit35","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/cr.2016.40","article-title":"Ubiquitin signaling\nin immune responses","volume":"26","author":"Hu","year":"2016","journal-title":"Cell Res."},{"issue":"9","key":"2026091109075484000_cit36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007296","article-title":"The papain-like\nprotease determines a virulence trait\nthat varies among members of the SARS-coronavirus species","volume":"14","author":"Niemeyer","year":"2018","journal-title":"PLoS Pathog."},{"issue":"21","key":"2026091109075484000_cit37","doi-asserted-by":"publisher","first-page":"4203","DOI":"10.1016\/j.jmb.2019.03.013","article-title":"ISG15: It\u2019s\nComplicated","volume":"431","author":"Dzimianski","year":"2019","journal-title":"J. Mol. Biol."},{"key":"2026091109075484000_cit38","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05378","article-title":"Unprecedented\ngenomic diversity of RNA viruses in arthropods reveals the ancestry\nof negative-sense RNA viruses","volume":"4","author":"Li","year":"2015","journal-title":"Elife"},{"issue":"3","key":"2026091109075484000_cit39","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.05340-22","article-title":"Diversity Analysis of Tick-Borne\nViruses from Hedgehogs and Hares in Qingdao, China","volume":"11","author":"Hu","year":"2023","journal-title":"Microbiol. Spectrum."},{"issue":"2","key":"2026091109075484000_cit40","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01727-24","article-title":"Characteristics\nof viral ovarian\ntumor domain protease from two emerging orthonairoviruses and identification\nof Yezo virus human infections in northeastern China as early as 2012","volume":"99","author":"Chen","year":"2025","journal-title":"J. Virol."},{"issue":"12","key":"2026091109075484000_cit41","doi-asserted-by":"publisher","first-page":"5954","DOI":"10.1002\/jmv.28089","article-title":"Discovery\nof a small-molecule inhibitor targeting the ovarian tumor domain of\na novel Tamdy orthonairoviruse associated with human febrile illness","volume":"94","author":"Li","year":"2022","journal-title":"J. Med. Virol."},{"issue":"23","key":"2026091109075484000_cit42","doi-asserted-by":"publisher","first-page":"e01067-17","DOI":"10.1128\/JVI.01067-17","article-title":"Structurally\nGuided Removal of DeISGylase Biochemical Activity from Papain-Like\nProtease Originating from Middle East Respiratory Syndrome Coronavirus","volume":"91","author":"Daczkowski","year":"2017","journal-title":"J. Virol."},{"issue":"8","key":"2026091109075484000_cit43","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1089\/vbz.2023.0029","article-title":"Molecular Detection\nof Tacheng Tick Virus-1 (TcTV-1) and Jingmen Tick Virus in Ticks Collected\nfrom Wildlife and Livestock in Turkey: First Indication of TcTV-1\nBeyond China","volume":"23","author":"Dincer","year":"2023","journal-title":"Vector-Borne Zoonotic Dis."},{"issue":"7873","key":"2026091109075484000_cit44","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein\nstructure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"issue":"5","key":"2026091109075484000_cit45","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1002\/pro.2637","article-title":"Inherent dynamics within the Crimean-Congo\nHemorrhagic fever virus protease are localized to the same region\nas substrate interactions","volume":"24","author":"Eisenmesser","year":"2015","journal-title":"Protein Sci."},{"issue":"1","key":"2026091109075484000_cit46","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/BF02100041","article-title":"Ubiquitin genes\nas a paradigm of concerted evolution of tandem repeats","volume":"25","author":"Sharp","year":"1987","journal-title":"J. Mol. 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