{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T06:47:15Z","timestamp":1770619635830,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,20]]},"group-title":"Microbiology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["CA285192"],"award-info":[{"award-number":["CA285192"]}]},{"name":"NIH","award":["AI184716"],"award-info":[{"award-number":["AI184716"]}]},{"name":"NIH","award":["AI180537"],"award-info":[{"award-number":["AI180537"]}]},{"name":"Herman Ostrow School of Dentistry of USC","award":["Startup funds"],"award-info":[{"award-number":["Startup funds"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Herpesviruses are common pathogens of the oral cavity, yet how they interact with other oral microbes are poorly understood. Using murine gamma-herpesvirus 68 (MHV68) as a model for human gamma-herpesviruses, we discover that ISGylation is hijacked to facilitate viral capsid assembly and lytic replication. Co-infection with the oral\n                  <jats:italic>Aggregatibacter actinomycetemcomitans<\/jats:italic>\n                  (\n                  <jats:italic>A.a<\/jats:italic>\n                  .) and MHV68 synergistically induced interferon-stimulated gene 15 (ISG15) expression and global ISGylation. Proteomic profiling revealed viral structural proteins as the dominant targets of ISGylation in MHV68-infected cells. Genetic ablation of ISGylation, using ISGylation-resistant recombinant MHV68 and ISG15-deficient mouse embryonic fibroblasts (MEFs), demonstrated that ISGylation of the major capsid protein ORF25 is required for efficient capsid assembly and maturation into the infectious C-type virions. Strikingly, introduction of a\n                  <jats:italic>de novo<\/jats:italic>\n                  ISGylation site into the ISGylation-resistant MHV68 was sufficient to restore ISGylation, capsid assembly, and virion maturation. Consistent with these findings,\n                  <jats:italic>A.a.<\/jats:italic>\n                  failed to enhance MHV68 lytic replication in ISG15-deficient MEFs. Extending this mechanism to representative herpesviruses, we showed that ISGylation of major capsid proteins is broadly required for efficient lytic replication. Together, these findings uncover a previously unrecognized strategy by which herpesviruses exploit an ISG15 innate immune effector, amplified by microbial co-infection, to promote virion biogenesis and productive infection.\n                <\/jats:p>","DOI":"10.64898\/2026.01.19.700396","type":"posted-content","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T03:05:16Z","timestamp":1768964716000},"source":"Crossref","is-referenced-by-count":0,"title":["Bacteria-herpesvirus interaction reveals a proviral role of ISGylation in promoting herpesvirus capsid assembly"],"prefix":"10.64898","author":[{"given":"Shutong","family":"Li","sequence":"first","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Cancer Metabolism, Beckman Research Institute of City of Hope; Duarte, 91010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongzhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Qin","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianglin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeru","family":"Saito","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; 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Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Yeh","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Tjokro","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biological Sciences, Dornsife College of Arts, Letters and Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Munger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Rochester, Rochester, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic, Cleveland, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey","family":"Chen","sequence":"additional","affiliation":[{"name":"Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California; 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