{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:49:14Z","timestamp":1785408554200,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,14]]},"group-title":"Microbiology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["2021-03035"],"award-info":[{"award-number":["2021-03035"]}],"id":[{"id":"https:\/\/ror.org\/03zttf063","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}]},{"name":"CDC Emerging Infectious Disease Research Core funds"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00ckakm23","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Union\u2019s HORIZON Research and Innovation Actions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,14]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Type I interferon (IFN-I) responses are tightly regulated to balance antiviral defense with cellular homeostasis. In humans, interferon-stimulated gene 15 (ISG15) functions as a critical negative regulator of IFN-I signaling by stabilizing the IFN negative regulator USP18, yet the functional consequences of ISG15 deficiency remain elusive. Here, we show that the loss of ISG15 exaggerates the JAK-STAT activation and, downstream, amplifies multiple ISGs including the nucleotide-modifying enzyme RSAD2 (viperin). Our quantitative proteomics, genetic reconstitution, and signaling analyses establish that defective USP18 stabilization skews the IFN response towards viperin expression. This amplified ISG network promotes viperin-catalyzed accumulation of the antiviral nucleotide analog ddhCTP, resulting in enhanced inhibition of viral RNA synthesis and the replication of Crimean-Congo hemorrhagic fever virus and SARS-CoV-2. Together, these findings demonstrate an ISG15-USP18-viperin axis that can be targeted to boost the metabolic antiviral restriction.<\/jats:p>","DOI":"10.64898\/2026.03.13.711570","type":"posted-content","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T04:45:13Z","timestamp":1773549913000},"source":"Crossref","is-referenced-by-count":0,"title":["ISG15-USP18 signaling restrains viperin-dependent metabolic antiviral restriction"],"prefix":"10.64898","author":[{"given":"Niklas L","family":"Kahler","sequence":"first","affiliation":[{"name":"Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Campus Flemingsberg, Karolinska Institutet, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sefanit","family":"Rezene","sequence":"additional","affiliation":[{"name":"Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Campus Flemingsberg, Karolinska Institutet, 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