PRRSV GP2a blocks the RLR signaling pathway by targeting RIG-I

ABSTRACT The strategy of viruses targeting RIG-I to disrupt the interferon (IFN) system represents an effective mechanism for evading innate immune responses. In this study, we observed that porcine reproductive and respiratory syndrome virus (PRRSV) GP2a inhibited IFN production by targeting RIG-I. Further studies revealed that GP2a blocks the RIG-I-like receptor signaling pathway through two mechanisms: (i) GP2a induces K48-linked ubiquitination of RIG-I by promoting the interaction between RIG-I and RING finger protein 125 (RNF125), resulting in RIG-I degradation, and (ii) GP2a hijacks zinc finger CCHC-type containing 3 (ZCCHC3) to disrupt the formation of the tripartite motif-containing 25 (TRIM25)-RIG-I complex, thereby inhibiting RIG-I K63-linked ubiquitination. This inhibition effectively prevents the activation and expression of RIG-I. In conclusion, our findings demonstrate novel mechanisms by which PRRSV GP2a inhibits IFN production, thereby improving our understanding of PRRSV immune evasion strategies. IMPORTANCE Porcine reproductive and respiratory syndrome is an important viral disease that affects the swine industry worldwide. PRRSV glycoproteins (GPs) play a crucial role in the viral infection process. However, it remains largely unknown about what roles PRRSV GPs play in antagonizing the innate immune response. In this study, we found that GP2a targets RIG-I to inhibit IFN production through a dual-faceted mechanism. GP2a promotes the RNF125-mediated degradation of RIG-I and competitively interacts with ZCCHC3 to impede TRIM25-induced RIG-I activation. This research contributes to a deeper understanding of the immune escape mechanisms employed by PRRSV.