NLRP12 通过 MARCH8 促进 GP2a 降解，从而抑制 PRRSV-2 的复制。

IF 2.4 2区农林科学 Q3 MICROBIOLOGY

Veterinary microbiology Pub Date : 2024-09-30 DOI:10.1016/j.vetmic.2024.110271

Huiyuan Jing , Yuzhen Song , Erzhen Duan , Jie Liu , Wenting Ke , Ran Tao , Yujin Lv , Pandeng Zhao , Wang Dong , Xianghui Li , Yongbin Guo , Huawei Li

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引用次数: 0

摘要

NLRP12 是 NLR 家族的成员之一，已被证明在协调免疫反应中发挥着重要功能。在这里，我们以免疫抑制猪繁殖与呼吸综合征病毒（PRRSV）为模型，解读了 NLRP12 在病毒感染中的作用。我们证明，过表达 NLRP12 能显著抑制 PRRSV 的复制，而沉默 NLRP12 则会导致病毒滴度增加。从机理上讲，NLRP12通过其LRR结构域与糖蛋白2a（GP2a）相互作用，并通过PYD结构域招募膜相关RING-CH E3泛素连接酶8（MARCH8）。NLRP12 促进了 GP2a 在 K128 处的赖氨酸-48 (K48) 链接多泛素化，并通过 MARCH8-NDP52（核点蛋白 52 kDa）途径诱导其溶酶体降解。为了对抗这种情况，PRRSV Nsp2 通过其去泛素化活性有效地阻止了 NLRP12 诱导的 GP2a 的多泛素化。同时，Nsp4的过表达降低了内源性NLRP12的mRNA，并以3C样蛋白酶活性依赖的方式裂解NLRP12，共同抵消了NLRP12的抗病毒功能。总之，本研究揭示了NLRP12-MARCH8-NDP52轴在宿主防御PRRSV中的作用机制，可用于开发抗PRRSV疗法。

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NLRP12 inhibits PRRSV-2 replication by promoting GP2a degradation via MARCH8

NLRP12, a member of the NLR family, has been shown to exert a vital function in orchestrating immune responses. Here, using the immunosuppressive porcine reproductive and respiratory syndrome virus (PRRSV) as a model, the role of NLRP12 in virus infection was deciphered. We demonstrated that overexpression of NLRP12 significantly restrained PRRSV replication, while NLRP12 silencing resulted in increased viral titer. Mechanistically, NLRP12 interacts with glycoprotein 2a (GP2a) through its LRR domain and recruits the membrane-associated RING-CH E3 ubiquitin ligase 8 (MARCH8) via the PYD domain. NLRP12 facilitates the lysine-48 (K48)–linked polyubiquitination of GP2a at K128 and induces its lysosome degradation via the MARCH8-NDP52 (nuclear dot protein 52 kDa) pathway. To counteract this, PRRSV Nsp2 effectively prevented the polyubiquitination of GP2a induced by NLRP12 by its deubiquitinating activity. Meanwhile, the overexpression of Nsp4 decreased the mRNA of endogenous NLRP12 and cleaved NLRP12 in a 3C-like protease activity-dependent manner, which collaboratively counteracts the antiviral function of NLRP12. Collectively, this study revealed the mechanisms of the NLRP12-MARCH8-NDP52 axis in the host defense against PRRSV, which might be harnessed for the development of anti-PRRSV therapies.

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来源期刊

Veterinary microbiology 农林科学-兽医学

CiteScore

5.90

自引率

6.10%

发文量

221

审稿时长

52 days

期刊介绍： Veterinary Microbiology is concerned with microbial (bacterial, fungal, viral) diseases of domesticated vertebrate animals (livestock, companion animals, fur-bearing animals, game, poultry, fish) that supply food, other useful products or companionship. In addition, Microbial diseases of wild animals living in captivity, or as members of the feral fauna will also be considered if the infections are of interest because of their interrelation with humans (zoonoses) and/or domestic animals. Studies of antimicrobial resistance are also included, provided that the results represent a substantial advance in knowledge. Authors are strongly encouraged to read - prior to submission - the Editorials (''Scope or cope'' and ''Scope or cope II'') published previously in the journal. The Editors reserve the right to suggest submission to another journal for those papers which they feel would be more appropriate for consideration by that journal. Original research papers of high quality and novelty on aspects of control, host response, molecular biology, pathogenesis, prevention, and treatment of microbial diseases of animals are published. Papers dealing primarily with immunology, epidemiology, molecular biology and antiviral or microbial agents will only be considered if they demonstrate a clear impact on a disease. Papers focusing solely on diagnostic techniques (such as another PCR protocol or ELISA) will not be published - focus should be on a microorganism and not on a particular technique. Papers only reporting microbial sequences, transcriptomics data, or proteomics data will not be considered unless the results represent a substantial advance in knowledge. Drug trial papers will be considered if they have general application or significance. Papers on the identification of microorganisms will also be considered, but detailed taxonomic studies do not fall within the scope of the journal. Case reports will not be published, unless they have general application or contain novel aspects. Papers of geographically limited interest, which repeat what had been established elsewhere will not be considered. The readership of the journal is global.