African swine fever virus MGF_110-8L promotes host cell autophagy and suppresses interferon signaling by activating the unfolded protein response.

Abstract

African swine fever virus (ASFV) infection induces cellular stress that activates the unfolded protein response (UPR), a key pathway for restoring endoplasmic reticulum (ER) homeostasis. However, the mechanisms by which ASFV modulates the UPR remain incompletely understood. Here, we identify the ASFV protein MGF_110-8L as a key regulator of the UPR, leading to the dissociation and activation of the UPR sensors PERK, IRE1α, and ATF6, which subsequently restore ER homeostasis. Moreover, MGF_110-8L triggers UPR-dependent autophagy, which in turn contributes to the suppression of type I interferon-mediated immune responses. Deletion of MGF_110-8L (ASFV-Δ8 L) markedly reduced the activation of both UPR and autophagy pathways and led to enhanced type I interferon responses. Together, our findings reveal a novel mechanism by which an ASFV protein activates the host UPR-autophagy axis to restore cellular homeostasis and modulate host innate immunity, highlighting MGF_110-8L as a potential target for therapeutic development.