Endoplasmic reticulum stress activated by IBRV induces mitophagy to impair the RIG-I-MAVS-mediated type I interferon pathway and facilitate viral replication.

Abstract

Infectious bovine rhinotracheitis (IBR) is a globally recognized infectious disease. The causative agent infects the respiratory and reproductive tracts of cattle, resulting in substantial economic losses to the cattle industry. Endoplasmic reticulum stress (ERS) and mitophagy play critical roles in maintaining cellular homeostasis during viral infections. However, whether Infectious bovine rhinotracheitis virus (IBRV) infection activates ERS and regulates the initiation of mitophagy remains unclear. In this study, IBRV infection robustly activates the ERS unfolded protein response (UPR) pathway and concurrently induces mitophagy and the innate immune pathway mediated by RIG-I-MAVS. Pharmacological inhibition of ERS, 4-PBA significantly abrogated IBRV-induced mitophagy. Further investigations revealed that inhibition of PERK with GSK2606414 and IRE1 with STF-083010 reverse IBRV-induced mitophagy, whereas the ATF6 inhibitor AEBSF had no such effect. Collectively, these findings suggested that IBRV-induced ER stress promotes mitophagy, at least in part, through the PERK and IRE1 pathways. Additionally, the mitophagy induced by IBRV may be related to the weakened transmission of type I interferon pathway mediated by RIG-I-MAVS, thereby establishing a permissive intracellular microenvironment for viral replication. These results implied the mechanism by which IBRV facilitates self-replication by impairing innate immunity through the induction of endoplasmic reticulum stress-mediated activation of mitophagy, likely offering novel insights for the prevention and control of IBRV infection.