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We and others previously reported that HSV type 2 (HSV-2) inhibits the synthesis of type I IFNs, but how HSV-2 suppresses IFN-mediated signaling is less understood. In the current study, after the demonstration of HSV-2 replication resistance to IFN-\u03b2 treatment in human epithelial cells, we reveal that HSV-2 and the viral protein ICP22 significantly decrease the expression of ISG54 at both mRNA and protein levels. Likewise, us1 del HSV-2 (ICP22-deficient HSV-2) replication is more sensitive to IFN-\u03b2 treatment, indicating that ICP22 is a vital viral protein responsible for the inhibition of type I IFN\u2013mediated signaling. In addition, overexpression of HSV-2 ICP22 inhibits the expression of STAT1, STAT2, and IFN regulatory factor 9 (IRF9), resulting in the blockade of ISG factor 3 (ISGF3) nuclear translocation, and mechanistically, this is due to ICP22-induced ubiquitination of STAT1, STAT2, and IRF9. HSV-2 ICP22 appears to interact with STAT1, STAT2, IRF9, and several other ubiquitinated proteins. Following further biochemical study, we show that HSV-2 ICP22 functions as an E3 ubiquitin protein ligase to induce the formation of polyubiquitin chains. Taken together, we demonstrate that HSV-2 interferes with type I IFN\u2013mediated signaling by degrading the proteins of ISGF3, and we identify HSV-2 ICP22 as a novel E3 ubiquitin protein ligase to induce the degradation of ISGF3. Findings in this study highlight a new mechanism by which HSV-2 circumvents the host antiviral responses through a viral E3 ubiquitin protein ligase.<\/jats:p>","DOI":"10.4049\/jimmunol.2000418","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T18:59:35Z","timestamp":1595444375000},"page":"1281-1292","source":"Crossref","is-referenced-by-count":30,"title":["Herpes Simplex Virus Type 2 Inhibits Type I IFN Signaling Mediated by the Novel E3 Ubiquitin Protein Ligase Activity of Viral Protein ICP22"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5164-5891","authenticated-orcid":false,"given":"Mudan","family":"Zhang","sequence":"first","affiliation":[{"name":"The Joint Laboratory of Translational Precision Medicine, Guangzhou Women and Children\u2019s Medical Center , Guangzhou 510623 ,","place":["China"]},{"name":"The Joint Laboratory of Translational Precision Medicine, Wuhan Institute of Virology, Chinese Academy of Sciences , Wuhan 430071 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2734-6725","authenticated-orcid":false,"given":"Ming","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , Wuhan 430071 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , Wuhan 430071 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , Wuhan 430071 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing 100049 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6899-0616","authenticated-orcid":false,"given":"Sitang","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University , Guangzhou 440106 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4594-9215","authenticated-orcid":false,"given":"Qinxue","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences , Wuhan 430071 ,","place":["China"]},{"name":"Institute for Infection and Immunity, St George\u2019s University of London , London SW17 0RE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,1]]},"reference":[{"key":"2025030417504827300_r1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1000991","article-title":"Plus- and minus-end directed microtubule motors bind simultaneously to herpes simplex virus capsids using different inner tegument structures","volume":"6","author":"Radtke","year":"2010","journal-title":"PLoS Pathog."},{"key":"2025030417504827300_r2","doi-asserted-by":"crossref","first-page":"4343","DOI":"10.1128\/JVI.75.9.4343-4356.2001","article-title":"Multiple immediate-early gene-deficient herpes simplex virus vectors allowing efficient gene delivery to neurons in culture and widespread gene delivery to the central nervous system in vivo","volume":"75","author":"Lilley","year":"2001","journal-title":"J. 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