猪呼吸与生殖综合征(PRRS)是猪最具破坏性的传染病之一,导致母猪繁殖失败,仔猪和生长猪出现严重的呼吸道症状。据报道,微RNA(miRNA)在病毒与宿主的相互作用中起着至关重要的作用。在这项研究中,我们证明miR-451通过靶向蛋白酶体亚基β8(PSMB8)增强I型干扰素(IFN-I)的产生,因此限制了PRRS病毒(PRRSV)的复制。我们发现PSMB8的表达被PRRSV感染上调,和敲除PSMB8通过促进IFN-I产生抑制PRRSV复制。此外,我们证明PSMB8与IRF3的调节域相互作用以介导K48连接的多泛素化和IRF3的降解。此外,重要的是,我们发现PSMB8作为miR-451的靶基因,通过促进IRF3降解负调控IFN-I的产生,这是以前未知的PSMB8调节先天免疫反应的机制。
目的:猪呼吸与生殖综合征病毒(PRRSV),作为对养猪业的巨大威胁,是急需解决的致病因素。PRRSV发病机理的解剖和对宿主-病原体相互作用的理解将为开发有效的抗PRRSV策略提供见解。在这项研究中,我们发现miR-451通过靶向蛋白酶体亚基β8(PSMB8)显著抑制PRRSV复制,免疫蛋白酶体的一个亚单位。PSMB8的突变通常与由于IFN产生升高的自身炎性疾病有关。我们发现PSMB8通过促进IRF3降解来下调IFN的产生。此外,我们显示PRRSV感染上调PSMB8表达。一起来看,我们的研究结果表明,miR-451是PRRSV复制的负调节因子,和PSMB8,miR-451的靶基因,通过促进IRF3降解负调控IFN-I的产生,这是以前未知的PSMB8调节先天免疫反应的机制。
Porcine respiratory and reproductive syndrome (PRRS) is one of the most devastating infectious diseases of pigs, causing reproductive failures in sows and severe respiratory symptoms in piglets and growing pigs. MicroRNAs (miRNAs) are reported to play an essential role in virus-host interactions. In this study, we demonstrated that miR-451 enhanced type I interferon (IFN-I) production through targeting proteasome subunit β8 (PSMB8), therefore restricting PRRS virus (PRRSV) replication. We showed that the expression of PSMB8 was upregulated by PRRSV infection, and knockdown of PSMB8 inhibited PRRSV replication by promoting IFN-I production. Moreover, we demonstrated that PSMB8 interacted with the regulatory domain of IRF3 to mediate K48-linked polyubiquitination and degradation of IRF3. Also, importantly, we showed that PSMB8, as a target gene of miR-451, negatively regulated IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to modulate innate immune responses.
OBJECTIVE: Porcine respiratory and reproductive syndrome virus (PRRSV), as a huge threat to the swine industry, is a causative agent that urgently needs to be solved. The dissecting of PRRSV pathogenesis and understanding of the host-pathogen interaction will provide insights into developing effective anti-PRRSV strategies. In this study, we showed that miR-451 dramatically inhibited PRRSV replication by targeting proteasome subunit β8 (PSMB8), a subunit of the immunoproteasome. Mutation of PSMB8 is often related to autoinflammatory diseases due to the elevated IFN production. We revealed that PSMB8 downregulated IFN production by promoting IRF3 degradation. In addition, we showed that PRRSV infection upregulated PSMB8 expression. Taken together, our findings reveal that miR-451 is a negative regulator of PRRSV replication, and PSMB8, a target gene of miR-451, negatively regulates IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to regulate innate immune responses.