{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T16:55:17Z","timestamp":1773939317072,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,17]]},"group-title":"Cell Biology","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>TRIM21 is a multifunctional E3 ubiquitin ligase and intracellular antibody receptor, yet its role during viral infection remains unclear, with reports describing both antiviral and proviral activities. Here, we show that TRIM21 regulates influenza infection in an expression-dependent manner by functioning as a molecular rheostat rather than a binary restriction factor. This graded activity of TRIM21, which leads to both suppression and promotion of influenza replication, couples linkage-specific ubiquitination of viral nucleoprotein with modulation of innate immune signaling. Additionally, loss of TRIM21 unmasks a compensatory antiviral program centered on PRKDC, which is a ubiquitination target of TRIM21. This positions PRKDC as a latent restriction factor selectively engaged when primary TRIM21 control is lost. Together, these findings reveal a hierarchical and plastic antiviral network in which TRIM21 sets an adjustable threshold for host defense while restraining secondary restriction pathways. This framework highlights the sophisticated layers of regulation of the host ubiquitin-mediated antiviral immunity.<\/jats:p>","DOI":"10.64898\/2026.03.16.711963","type":"posted-content","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T13:10:15Z","timestamp":1773753015000},"source":"Crossref","is-referenced-by-count":0,"title":["TRIM21 is a molecular rheostat for influenza A virus replication"],"prefix":"10.64898","author":[{"given":"Qi Wen","family":"Teo","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huibin","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tossapol","family":"Pholcharee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vidia","family":"Ramadin","sequence":"additional","affiliation":[{"name":"Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin J.","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica J.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Rivera-Cardona","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang Wei","family":"Huan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan K.","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hein M.","family":"Tun","sequence":"additional","affiliation":[{"name":"Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6815-1193","authenticated-orcid":false,"given":"Christopher B.","family":"Brooke","sequence":"additional","affiliation":[{"name":"Carl R. 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