The alpha-coronavirus E protein inhibits the JAK-STAT pathway signaling by triggering STAT2 degradation through OPTN- and NBR1-mediated selective autophagy

作者：Zhao Huang, Chenyang Gao, Shaohong Huang, Sizhan Lin, Wenbo Zhang, Jianyi You, Xiongnan Chen, Pei Zhou, Guihong Zhang, Lang Gong · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2479671 · 被引用次数：8 · 研究领域：Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease、Immune Cell Function and Interaction

The zoonotic transmission of coronaviruses continues to pose a considerable threat to humans. Swine acute diarrhea syndrome coronavirus (SADS-CoV), a bat coronavirus related to HKU2, causes severe economic losses in the pig industry and has the potential to trigger outbreaks in humans. However, our understanding of how SADS-CoV evades the host’s innate immunity remains limited, hindering effective responses to potential human outbreaks. In this study, we demonstrate that the SADS-CoV envelope protein (E) inhibits type I interferon (IFN-I) signaling by inducing the degradation of STAT2 via the macroautophagy/autophagy-lysosome pathway. Mechanistically, the E protein evades host innate immunity by promoting STAT2 degradation through autophagy, mediated by the NBR1 and OPTN receptors. Notably, ubiquitination of E protein is required for the autophagic degradation of STAT2. Additionally, lysine residue K61 of the E protein is crucial for its stable expression; however, it is not involved in its ubiquitination. In conclusion, our study reveals a novel mechanism by which the E protein disrupts IFN-I signaling by targeting STAT2 via autophagy, enhancing our understanding of SADS-CoV’s immune evasion strategies and providing potential drug targets for controlling viral infections.Abbreviations: 3-MA: 3-methyladenine; ATG: autophagy related; BafA1: bafilomycin A1; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CC: coiled-coil; CHX: cycloheximide; ...