PRRSV Nsp2 promotes inflammatory responses by restricting ER-to-Golgi translocation of STING through HMGB1.

STING serves as a central adaptor in innate immunity, with its trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus determining its signaling outcomes. Retention of STING within the ER is associated with enhanced inflammatory responses, whereas its localization to the Golgi apparatus facilitates the production of type I interferon. In this study, we demonstrate that porcine reproductive and respiratory syndrome virus (PRRSV), an economically significant swine pathogen characterized by causing interstitial pneumonia, promotes the retention of STING within the ER, thereby enhancing inflammatory responses. Mechanistically, high mobility group box 1 (HMGB1) mediates PRRSV-induced impairment of STING trafficking. Conversely, the knockout of HMGB1 restores STING localization to the Golgi apparatus and attenuates proinflammatory cytokine expression. Furthermore, we identify PRRSV nonstructural protein 2 (Nsp2) as a viral determinant that amplifies inflammatory responses through the HMGB1-STING axis. Nsp2 facilitates HMGB1-dependent impairment of STING trafficking, thereby reinforcing inflammatory responses. Collectively, our study identifies the spatial regulation of STING as a novel mechanism exploited by PRRSV to bias immune signaling toward inflammation, providing new insights into viral pathogenesis.