数字农科院2.0

GRP75 blocks hepatitis E virus infection by targeting HEV-ORF2 for degradation through chaperone-mediated autophagy and promoting IRF3 activation

文献类型： 外文期刊

作者： Wang, Yajing;Li, Yafei;Xu, Rong;Yuan, Tong;Xu, Chenying;Zhou, Zhaobin;Ba, Cuiyu;Zhao, Qin;Wu, Chunyan;An, Zhiru;Yin, Xin;Yang, Yonglin;Nan, Yuchen

作者机构：

关键词： CMA;GRP75;hepatitis E virus (HEV);interferon;mitochondria;ORF2

期刊名称： JOURNAL OF VIROLOGY

ISSN： 0022-538X

年卷期： 2025 年

页码：

收录情况： SCIE（2025版）

摘要： Hepatitis E virus (HEV) is a viral hepatitis pathogen that poses a significant threat to global human health, representing a serious yet long-overlooked public health concern. In this study, we identified glucose-regulated protein 75 (GRP75) as an interaction partner of HEV-ORF2 using recombinant ORF2 truncation as bait. The substrate-binding domain of GRP75 interacted with HEV-ORF2 and inhibited HEV replication by facilitating HEV-ORF2 degradation. Further analysis revealed that HEV-ORF2 contains three KFERQ-like motifs, the key signature sequence required for chaperone-mediated autophagy (CMA). Our data demonstrated that GRP75-mediated degradation of HEV-ORF2 was heat-shock cognate protein 70 (HSC70)-dependent, although no direct interaction between HSC70 and ORF2 was detected. Instead, GRP75, together with HEV-ORF2 and HSC70, formed a complex that mediated CMA-dependent degradation of HEV-ORF2, whereas deletion of all three KFERQ-like motifs from ORF2 conferred resistance to such processes. Additionally, GRP75 blocked mitochondrial transport of HEV-ORF2, potentially mitigating ORF2's function as an interferon (IFN) induction antagonist. Furthermore, GRP75 enhanced the interaction between mitochondrial antiviral signaling protein (MAVS) and TANK-binding kinase 1 (TBK1), promoting IFN-beta production and ultimately inhibiting HEV infection. In conclusion, our findings identify GRP75 as a novel restriction factor for HEV infection and provide new insights into its role in CMA and antiviral innate immunity.IMPORTANCEDue to the lack of an effective in vitro model, the viral-host interaction of HEV remains largely elusive. This study uncovers a novel mechanism by which GRP75 inhibits HEV infection. On one hand, the GRP75 protein facilitates the degradation of HEV-ORF2 through the lysosome-associated, chaperone-mediated autophagy by recognizing KFERQ-like motif presented on HEV-ORF2. On the other hand, GRP75 enhances the production of IFN-beta by promoting interaction between MAVS and TBK1, thereby establishing an antiviral state and suppressing HEV infection. This research expands our current understanding of host resistance to HEV and provides a new function of GRP75, suggesting that GRP75 might be a novel antiviral factor against virus infection.

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