. doi: 10.1016/j.virs.2024.01.005
Citation: Ruiqi Sun, Yanyu Guo, Lilin Zhang, Huixia Zhang, Boxuan Yin, Xiaoyang Li, Changyan Li, Liu Yang, Lei Zhang, Zexing Li, Jinhai Huang. PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity .VIROLOGICA SINICA, 2024, 39(2) : 264-276.  http://dx.doi.org/10.1016/j.virs.2024.01.005

PRRSV通过双重自噬受体P62和CCT2降解MDA5逃避抗病毒先天免疫反应

  • 猪繁殖与呼吸综合征病毒(PRRSV)是一种对经济产生严重破坏的主要病原体,已经进化出多种策略以逃避先天免疫。通过胞质内黑色素瘤分化相关基因5(MDA5)-一种感知病毒RNA的受体来降低抗病毒干扰素的表达,从而在很大程度上助长了PRRSV的免疫逃逸。在本研究中,我们观察到猪MDA5在PRRSV感染中转录和表达水平下调,但具体机制仍然不清楚。PRRSV感染细胞中,受到上调的激酶CK2α的作用,强化了自噬受体P62的磷酸化修饰并促进其与MDA5的相互作用,且E3泛素连接酶TRIM21引起的猪MDA5的K63泛素化,从而触发了经典的P62介导的自噬。此外,猪MDA5与含TCP1亚基2(CCT2)的分子伴侣相互作用,PRRSV编码的 nsp3促进它们的结合,促进了MDA5-CCT2-nsp3聚集体的形成和自噬清除,这一过程不依赖泛素。总之,PRRSV感染中通过两种自噬途径增强了MDA5的降解,包括MDA5与自噬受体P62以及聚集体自噬受体CCT2的结合,触发了强烈的先天免疫抑制。本研究揭示了PRRSV感染中免疫逃避的一种新机制,并为开发新疫苗或治疗药物提供了基础见解。

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity

  • Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

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    PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity

    Abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

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