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Therefore, it is necessary to investigate the immune escape strategies employed by GCRV. In this study, we show that the structural protein VP4 of GCRV (encoded by the S6 segment) significantly restricts IFN expression by degrading stimulator of IFN genes (STING) through the autophagy-lysosome-dependent pathway. First, overexpression of VP4 inhibited the expression of IFN induced by GCRV and polyinosinic-polycytidylic acid (poly I:C) at both the promoter and mRNA levels. Second, VP4 was found to associate with STING, and the N-terminal transmembrane domain is essential for this interaction. Additionally, VP4 dramatically blocked STING-induced IFN expression and weakened its antiviral capacity. Further mechanistic studies revealed that VP4 degrades STING via the autophagy-lysosome pathway in a dose-dependent manner. Interestingly, toll-interacting protein (TOLLIP), a selective autophagy receptor, was found to interact with VP4 and reduce VP4-mediated STING degradation after\n              <jats:italic>tollip<\/jats:italic>\n              knockdown. Finally, overexpression of VP4 facilitated GCRV proliferation, while its depletion had the opposite effect. These findings indicate that GCRV VP4 recruits TOLLIP to degrade STING and achieve immune escape. This enhances our comprehension of aquatic virus pathogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Upon virus invasion, fish cells employ a multitude of strategies to defend against infection. Consequently, viruses have evolved a plethora of tactics to evade host antiviral mechanisms. To date, fewer studies have been conducted on the immune evasion mechanism of grass carp reovirus (GCRV). In this study, we demonstrate that VP4 of GCRV-873 inhibits interferon expression by interacting with stimulator of IFN gene and degrading it in an autophagy-lysosome-dependent manner through the manipulation of the selective autophagy receptor toll-interacting protein. The findings of this study contribute to our understanding of the novel evasion mechanisms of GCRV and widen our knowledge of the virus-host interactions in lower vertebrates.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01583-24","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T14:01:13Z","timestamp":1736863273000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Grass carp reovirus VP4 manipulates TOLLIP to degrade STING for inhibition of IFN production"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9565-6139","authenticated-orcid":false,"given":"Yang-Yang","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Hydrobiology, Chinese Academy of Sciences","place":["Wuhan, China"]},{"name":"University of Chinese Academy of Sciences","place":["Beijing, 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