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

文献类型： 外文期刊

第一作者： Jing, Huiyuan

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

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关键词： Porcine reproductive and respiratory syndrome; virus (PRRSV); NLR family pyrin domain containing 12; (NLRP12); Membrane-associated RING-CH E3 ubiquitin; ligase 8 (MARCH8); Glycoprotein 2a (GP2a); Nonstructural protein (Nsp) 2; Nsp4

期刊名称：VETERINARY MICROBIOLOGY （ 影响因子：2.7； 五年影响因子：2.9 ）

ISSN： 0378-1135

年卷期： 2024 年 298 卷

页码：

收录情况： SCI

摘要： 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 MARCH8NDP52 (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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