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

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

  • Autophagy. 2025 Mar 30:1-18. doi: 10.1080/15548627.2025.2479671.
Zhao Huang 1 2 Chenyang Gao 1 2 Shaohong Huang 1 2 Sizhan Lin 1 2 WenBo Zhang 1 Jianyi You 1 Xiongnan Chen 1 2 Pei Zhou 1 3 Guihong Zhang 1 3 Lang Gong 1 3
Affiliations

Affiliations

  • 1 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • 2 Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China.
  • 3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China.
Abstract

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; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; DBD: DNA-binding domain; DMEM: Dulbecco's Modified Eagle's medium; DMSO: dimethyl sulfoxide; E, Envelope. FW: four-tryptophan; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HA: hemagglutinin; hpt: hours post-treatment; IF: indirect immunofluorescence; IFNB/IFN-β: interferon beta; IgG: immunoglobulin G; ISG: IFN-stimulated genes; ISRE: interferon-stimulated response element; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; NBR1: NBR1 Autophagy cargo receptor; OPTN: optineurin; PBS: phosphate-buffered saline; PRRs: pattern recognition receptors; qPCR: quantitative polymerase chain reaction; SAR: selective Autophagy receptor; SQSTM1/p62: sequestosome 1; STAT: signal transduction and activator of transcription; TBS-T: Tris-buffered saline with Tween 20; TCID50: 50% tissue culture infective dose; TOLLIP: toll interacting protein; Ub: ubiquitin; UBA: C-terminal ubiquitin-associated; VSV: vesicular stomatitis virus; WB: western blotting. WT: wild type.

Keywords

Alpha-coronaviruses; STAT2; envelope; innate immunity; selective autophagy host.

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