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Rotaviruses have evolved a repertoire of viral proteins to counteract host immune surveillance. While certain functions of rotavirus nonstructural proteins in antagonizing IFN\u2010I signaling have been characterized, the precise molecular mechanism by which nonstructural protein 4 (NSP4) impairs host immunity remains elusive. Here, we demonstrated that the porcine rotavirus (PoRV) nonstructural protein NSP4 potently suppresses the transcriptional activation of interferon\u2010stimulated genes (ISGs), IFN\u2010\u03b2 promoters, and interferon\u2010sensitive response elements (ISREs) while abrogating the phosphorylation of interferon regulatory factor 3 (IRF3). Mechanistically, NSP4 promotes the degradation of melanoma differentiation\u2010associated gene 5 (MDA\u20105) via nuclear receptor binding factor 2 (NRBF2)\u2010dependent autophagy, thereby subverting IFN\u2010I production. The validity of this mechanism in primary epithelial cells was also verified by constructing an intestinal organoid model in piglets. Collectively, our findings elucidate a previously unrecognized immune evasion mechanism by which NSP4 antagonizes the IFN\u2010I\u2010mediated antiviral response, providing novel molecular insights for developing therapeutic strategies against rotavirus infections.<\/jats:p>","DOI":"10.1155\/tbed\/5789277","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T08:05:12Z","timestamp":1782288312000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Porcine Rotavirus NSP4 Inhibits Type I Interferon Production via NRBF2\u2010Mediated Autophagic Degradation of 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