African swine fever virus pA137R inhibits type i interferon signal transduction by interacting with TYK2 and impairing STAT1/2 activation.

Abstract

African swine fever virus (ASFV) pA137R is a key immune evasion protein known to target TBK1 and suppress the cGAS-STING pathway; however, whether it modulates type I interferon (IFN) signal transduction remains unknown. In this study, we investigated the role of the A137R protein (pA137R) in the JAK-STAT type I IFN signaling cascade. We found that pA137R directly interacts with TYK2 via a 10-amino-acid motif (aa81-90), interferes with the IFNAR1-TYK2 interaction. This disruption inhibited the phosphorylation and nuclear translocation of both STAT1 and STAT2, leading to a pronounced suppression of interferon-stimulated gene (ISG) expression. Consistently, an A137R-deleted ASFV strain displayed markedly enhanced sensitivity to IFN stimulation and produced significantly higher levels of ISGs compared to the parental virus. Collectively, these findings identify pA137R as a potent antagonist of the JAK-STAT pathway that, by targeting TYK2, blocks STAT1/2 activation and ISG induction. This work reveals a previously unrecognized mechanism by which this virulence factor disarms type I IFN-mediated innate antiviral responses and, together with its known activity against cGAS-STING, underscores the pivotal role of A137R in ASFV immune evasion.