Porcine astrovirus induces endoplasmic reticulum stress-mediated autophagic degradation of MAVS to inhibit type I interferon production

Abstract

Porcine astrovirus (PAstV) infection predominantly results in diarrhea and encephalitis in suckling piglets, yet the underlying pathogenic mechanisms remain poorly understood. In this study, the PAstV1-GX1 strain, previously isolated, was utilized to infect PK-15 cells. The results demonstrated that PAstV infection induced pronounced endoplasmic reticulum (ER) stress, as evidenced by the upregulation of HSPA5/GRP78 expression, and macroautophagy/autophagy, indicated by the increased conversion of MAP1LC3/LC3 from LC3-I to LC3-II and decreased expression of SQSTM1/p62. Pharmacological mitigation of ER stress effectively suppressed autophagy, suggesting that PAstV facilitates autophagy via ER stress. Further mechanistic investigations identified that PAstV infection selectively activated the EIF2AK3/PERK-EIF2S1/eIF2α-ATF4 pathway within the unfolded protein response, establishing this pathway as the pivotal upstream signal mediating autophagy. Through the screening of viral proteins, the capsid protein was identified as the primary viral component responsible for inducing ER stress and autophagy. This protein was concurrently localized to both mitochondria and the ER, where it interacted with the MAVS (mitochondrial antiviral signaling protein). The capsid protein facilitated the degradation of MAVS via the autophagy pathway and an apoptosis-related pathway in a non-classical, caspase-3-independent manner, thereby suppressing the production of type I interferons. Modulating ER stress, autophagy, or apoptosis greatly impacted the capsid protein's suppression of type I interferons. This suggested that the capsid protein hindered type I interferon production by triggering ER stress, which activated autophagy and possibly apoptosis, resulting in MAVS degradation. These insights lay the groundwork for understanding PAstV's pathogenic mechanisms and aid in developing new antiviral treatments.

The authors' abstract, as published at the source. Autophagy, 2026 · DOI ↗