PDF(Pubmed)
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.
摘要：
猪繁殖与呼吸综合征病毒（PRRSV）是一种主要的经济破坏性病原体，已进化出各种策略来逃避先天免疫。抗病毒干扰素的下调很大程度上有助于PRRSV通过细胞质黑色素瘤分化相关基因5（MDA5）的免疫逃避，一种感知病毒RNA的受体。在这项研究中,观察猪MDA5在PRRSV感染中的转录和表达水平,但具体机制尚不清楚.在PRRSV感染的细胞中，由于上调的激酶CK2α对自噬受体P62的磷酸化修饰和E3泛素酶TRIM21催化的猪MDA5的K63泛素化，P62和MDA5之间的相互作用得到加强，从而触发经典的P62介导的自噬。此外,猪MDA5与含有TCP1亚基2（CCT2）的伴奏蛋白相互作用，并被PRRSVnsp3增强，促进了MDA5-CCT2-nsp3的聚集体形成和自噬清除，而与泛素无关。增强的MDA5降解发生在PRRSV感染通过两个自噬途径，包括MDA5与自噬受体P62和聚集性受体CCT2的结合，引发强烈的先天免疫抑制。该研究揭示了PRRSV感染中免疫逃避的新机制，并为开发新的疫苗或治疗策略提供了基本见解。
