猪繁殖与呼吸综合征病毒非结构蛋白2促进适配蛋白SH3KBP1的自噬降解,通过增强RIG-I的K63连接多泛素化来拮抗宿主先天性免疫反应。

IF 5.5 1区 医学 Q1 MICROBIOLOGY PLoS Pathogens Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012670
Jiaoyang Li, Jing Zhang, Pu Sun, Jian Wang, Guoxiu Li, Zhanding Cui, Dong Li, Hong Yuan, Tao Wang, Kun Li, Xingwen Bai, Zhixun Zhao, Yimei Cao, Xueqing Ma, Pinghua Li, Yuanfang Fu, Huifang Bao, Zaixin Liu, Shuqi Xiao, Xinglong Wang, Zengjun Lu
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引用次数: 0

摘要

PRRSV 的非结构蛋白 2(NSP2)具有高度可变性,在病毒的生命周期中起着至关重要的作用。为了阐明 NSP2 在 PRRSV 感染过程中的功能,我们利用质谱鉴定出 SH3KBP1 是与 NSP2 相互作用的宿主蛋白。外源 SH3KBP1 的表达通过增强 IFN-I 和相关 ISGs 的产生,显著抑制了 PRRSV 的复制。相反,SH3KBP1 基因敲除则通过下调 IFN-I 和 ISGs 水平促进病毒复制。体内实验显示,Sh3kbp1-/-小鼠对 VSV 感染更易感,血清 IFN-β 水平降低。进一步的研究表明,SH3KBP1 通过与 E3 泛素连接酶 TRIM25 相互作用,增加 K63 连接的多泛素化,从而增强 RIG-I 信号转导。我们还发现,PRRSV 感染和 NSP2 过表达会诱导 SH3KBP1 自噬降解,从而抵消宿主的先天免疫反应。在 NSP2 的第三个富脯氨酸基团(453PVPAPR458)中发现了一个关键的相互作用位点。缺乏该基序的重组 PRRSV 毒力减弱,SH3KBP1 降解减少。这项研究加深了我们对 PRRSV 如何干扰宿主免疫应答的理解,并为开发新型 PRRSV 减毒疫苗提供了宝贵的见解。
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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.

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-β 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 polyproline-arginine 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 developing novel attenuated vaccines against PRRSV.

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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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