Porcine reproductive and respiratory syndrome virus nonstructural protein 2 promotes the autophagic degradation of adaptor protein SH3KBP1 to antagonize host innate immune responses by enhancing K63-linked polyubiquitination of RIG-I

文献类型： 外文期刊

第一作者： Li, Jiaoyang

作者： Li, Jiaoyang;Zhang, Jing;Sun, Pu;Wang, Jian;Li, Guoxiu;Cui, Zhanding;Li, Dong;Yuan, Hong;Wang, Tao;Li, Kun;Bai, Xingwen;Zhao, Zhixun;Cao, Yimei;Ma, Xueqing;Li, Pinghua;Fu, Yuanfang;Bao, Huifang;Liu, Zaixin;Xiao, Shuqi;Lu, Zengjun;Li, Jiaoyang;Wang, Xinglong;Li, Jiaoyang;Zhang, Jing;Sun, Pu;Wang, Jian;Li, Guoxiu;Cui, Zhanding;Li, Dong;Yuan, Hong;Wang, Tao;Li, Kun;Bai, Xingwen;Zhao, Zhixun;Cao, Yimei;Ma, Xueqing;Li, Pinghua;Fu, Yuanfang;Bao, Huifang;Liu, Zaixin;Xiao, Shuqi;Lu, Zengjun

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：4.9； 五年影响因子：5.4 ）

ISSN： 1553-7366

年卷期： 2024 年 20 卷 10 期

页码：

收录情况： SCI

摘要： Non-structural protein 2 (NSP2) of PRRSV is highly variable and plays crucial roles in the virus's life cycle. To elucidate the function of NSP2 during PRRSV infection, we identified SH3KBP1 as an NSP2-interacting host protein using mass spectrometry. Exogenous SH3KBP1 expression significantly inhibited PRRSV replication by enhancing IFN-I and related ISGs production. Conversely, SH3KBP1 knockdown promoted viral replication by downregulating IFN-I and ISGs levels. In vivo experiments revealed that Sh3kbp1-/- mice were more susceptible to VSV infection, exhibiting reduced serum IFN-beta levels. Further investigation showed that SH3KBP1 enhances RIG-I signal transduction by increasing K63-linked polyubiquitination through interaction with the E3 ubiquitin ligase TRIM25. We also found that PRRSV infection and NSP2 overexpression induce the autophagic degradation of SH3KBP1, counteracting the host's innate immune response. A critical interaction site was identified within the third proline-rich motif in NSP2 (453PVPAPR458). Recombinant PRRSV lacking this motif displayed reduced virulence and decreased SH3KBP1 degradation. This study advances our understanding of how PRRSV interferes with the host immune response and offers valuable insights for development novel attenuated vaccines against PRRSV.

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