Picornavirus 3D polymerase inhibits antiviral innate immunity by blocking the activation of JAK-STAT signaling pathway.

Picornaviruses are known for their rapid replication rate, which is a key characteristic that allows them to quickly infect host cells and produce progeny viruses. The interactions with host cells established by the virus to bypass host defense are essential for their rapid replication. The 3D protein, identified as the RNA-dependent RNA polymerase (RdRp) of picornaviruses, is central to viral replication. In this study, we delineated a conserved strategy employed by picornavirus 3D proteins to counteract the antiviral response elicited by interferons. Senecavirus A (SVA) 3D protein targets and hijacks JAK1, a pivotal component of the innate immune cascade, thereby decreasing the expression of a spectrum of interferon-stimulated antiviral genes. The interaction between the N-terminal region of SVA 3D (amino acids 1-152) and the FERM domain of JAK1 is responsible for the suppression of JAK-STAT signaling. Mechanistically, SVA 3D recruits the E3 ubiquitin ligase RNF125, inducing the K48-linked polyubiquitination of JAK1 at K205 and K249, which ultimately leads to the proteasomal degradation of JAK1. 3D proteins from other picornaviruses (FMDV, EMCV, and EV71) also suppress JAK1-mediated antiviral response. Collectively, these findings elucidate the suppressive regulatory mechanisms of picornaviruses 3D, highlighting a prevalent immune evasion tactic among picornaviruses, which will provide insights for developing antiviral strategies against picornaviruses.IMPORTANCEPicornaviruses can establish interactions with host cells to bypass host defense mechanisms. The highly conserved viral polymerase 3D protein of picornavirus broadly inhibited JAK-STAT signaling and promoted viral replication. Specifically, SVA 3D induces the K48-linked ubiquitination of JAK1 through recruitment of the E3 ubiquitin ligase RNF125. Similarly, FMDV, EMCV, and EV71 3D proteins act as negative regulators to inhibit JAK-STAT pathway activation. These findings unveil a common immune suppression strategy employed by picornaviruses, thereby advancing our understanding of picornavirus pathogenesis and opening avenues for developing antiviral strategies against picornaviruses.