Seneca Valley Virus 2B and 3C proteins attenuate the cGAS-STING signaling pathway by targeting STING for degradation

Seneca Valley virus (SVV), an emerging porcine picornavirus, has attracted significant attention recently as it presents a substantial threat to the global pork industry. Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-associated adaptor protein that plays a crucial role in the type I interferon (IFN-I) signaling pathway, which triggers IFN-stimulated gene (ISG) production to elicit antiviral innate immunity. SVV has evolved numerous strategies to counteract the IFN-I signaling pathway and evade innate immunity. However, the mechanism underlying immune evasion in SVV infection remains unclear. In this study, we observed that SVV 2B and 3C proteins promoted STING degradation to antagonize IFN-I activation through autophagy and caspase pathways, respectively. Mechanistically, 2B bound to STING, recruiting toll-interacting protein (Tollip) and neighbor of BRCA1 gene 1 (NBR1) to promote STING for autophagy degradation, and 2B prevented the STING-TBK1 interaction. Furthermore, SVV 3C antagonized host IFN-I signaling by cleaving interferon-stimulated gene 60 (ISG60) at Gln-406. The cleaved ISG60 products failed to inhibit SVV infection. Collectively, our study uncovered that SVV subverts the IFN-I response by targeting STING and ISG60, providing deeper insights into a novel mechanism utilized by SVV to antagonize the host's innate immune response.