EGR1 functions as a new host restriction factor for SARS-CoV-2 to inhibit virus replication through the E3 ubiquitin ligase MARCH8

文献类型： 外文期刊

第一作者： Zhao, Yinghua

作者： Zhao, Yinghua;Sui, Liyan;Wang, Ze-Dong;Zhang, Kaiyu;Niu, Junqi;Liu, Quan;Zhao, Yinghua;Sui, Liyan;Wang, Ze-Dong;Zhang, Kaiyu;Niu, Junqi;Liu, Quan;Zhao, Yinghua;Wu, Ping;Liu, Li;Ma, Baohua;Hou, Zhijun;Liu, Quan;Li, Letian;Jin, Ningyi;Li, Chang;Wang, Wenfang;Chi, Hongmiao;Wang, Guoqing;Wei, Zhengkai;Liu, Quan;Zhao, Jixue;Liu, Quan

作者机构：

关键词： SARS-CoV-2; nucleocapsid protein; interferon; EGR1; IFN-regulated antiviral protein; MARCH8

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 0022-538X

年卷期： 2023 年

页码：

收录情况： SCI

摘要： Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an unprecedented public health crisis worldwide. Though the host produces interferons (IFNs) and restriction factors to suppress virus infection, SARS-CoV-2 has evolved multiple strategies to inhibit the antiviral responses. Understanding host restriction factors and viral escape mechanisms is conducive to developing effective anti-SARS-CoV-2 drugs. Here, we constructed SARS-CoV-2 nucleocapsid (2N) protein- and green fluorescent protein (GFP)-stably expressing cells that were transfected with polyinosinic-polycytidylic acid (poly(I:C)) to activate IFN responses. The transcriptome analysis showed that poly(I:C)-induced IFN responses were inhibited by the SARS-CoV-2 N protein. Further analysis revealed that 2N inhibited the production of IFN-stimulated genes by suppressing early growth response gene-1 (EGR1) expression, a transcription factor that can regulate multiple cellular processes. The ectopic expression of EGR1 remarkably reduced 2N expression and suppressed SARS-CoV-2 replication. Mechanistically, EGR1 promoted expression of IFN-regulated antiviral protein (IRAV), which interacted with 2N to induce its degradation via the E3 ubiquitin ligase MARCH8 with the cargo receptor NDP52 in a lysosome-dependent pathway. MARCH8 catalyzed the K48-linked polyubiquitination of 2N at the lysine residue 143, and knockout of endogenous MARCH8 reversed IRAV-mediated 2N degradation. Additionally, the overexpression of IRAV or MARCH8 could inhibit SARS-CoV-2 replication. Our findings reveal that EGR1 is a new host restriction factor to inhibit SARS-CoV-2 replication through the E3 ubiquitin ligase MARCH8, which would contribute to understanding the pathogenesis of emerging coronaviruses.

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