African swine fever virus E301R protein promotes RIG-I autophagic degradation by enhancing RIG-I-sequestosome-1 interaction.

African swine fever is a highly contagious disease caused by African swine fever virus (ASFV). The immune evasion capabilities of ASFV are crucial for its efficient replication within cells. As a DNA virus, the molecular mechanisms by which ASFV evades the cGAS-STING pathway have been extensively studied. However, the mechanisms underlying the evasion of dsRNA-activated pathways remain unclear. In this study, we aimed to identify the immunosuppressive function of ASFV E301R protein. We identified that pE301R strongly inhibits retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling and suppresses IFN-I production. pE301R impedes RLR signaling by directly degrading RIG-I, and pharmacological inhibition of autophagy rescued pE301R-induced RIG-I degradation. pE301R degrades RIG-I by promoting its interaction with p62. The siRNA-mediated knockdown of p62 rescued pE301R-mediated RIG-I degradation. In summary, our study demonstrates that pE301R degrades RIG-I via the autophagy pathway, thereby suppressing IFN-I production and aiding ASFV in evading the host's innate immune response. This finding enriches our understanding of the molecular mechanisms underlying the escape of ASFV from the RLR signaling pathway.