NLRC5 restricts dengue virus infection by promoting the autophagic degradation of viral NS3 through E3 ligase CUL2 (cullin 2)
NLRC5 restricts dengue virus infection by promoting the autophagic degradation of viral NS3 through E3 ligase CUL2 (cullin 2)
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DOI：
10.1080/15548627.2022.2126614
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发表时间：
2022-10-01
期刊：
影响因子：
13.3
通讯作者：
Li, Yi-Ping
中科院分区：
文献类型：
--
作者：
Hao, Jiawei;Li, Jinqian;Li, Yi-Ping
据报道，NLRC 5参与抗病毒免疫;然而，其潜在机制仍然知之甚少。在这里，我们研究了NLRC 5在黄病毒登革病毒（DENV）感染中的功能作用。我们发现，NLRC 5的表达强烈诱导病毒感染和IFNB或IFNG刺激在不同的细胞系。NLRC 5的过表达显著抑制DENV感染，而NLRC 5的敲除导致DENV感染的显著增加。机制研究表明，NLRC 5与病毒非结构蛋白3（NS 3）蛋白酶结构域相互作用，通过泛素依赖的选择性巨自噬/自噬途径介导NS 3的降解。我们证明，NLRC 5招募E3泛素连接酶CUL 2（cullin 2）催化K48连接的NS 3蛋白酶结构域的多聚泛素化，随后作为货物受体TOLLIP介导的选择性自噬降解的识别信号。总之，我们已经证明NLRC 5通过介导DENV的多功能蛋白的降解而发挥抗病毒作用，提供了NLRC 5-CUL 2-NS 3-TOLLIP的新的抗病毒信号轴。本研究扩展了我们对NLRC 5在宿主防御病毒感染中的调控网络的理解。
NLRC5 has been reported to be involved in antiviral immunity; however, the underlying mechanism remains poorly understood. Here, we investigated the functional role of NLRC5 in the infection of a flavivirus, dengue virus (DENV). We found that the expression of NLRC5 was strongly induced by virus infection and IFNB or IFNG stimulation in different cell lines. Overexpression of NLRC5 remarkably suppressed DENV infection, whereas knockout of NLRC5 led to a significant increase in DENV infection. Mechanistic study revealed that NLRC5 interacted with the viral nonstructural protein 3 (NS3) protease domain and mediated degradation of NS3 through a ubiquitin-dependent selective macroautophagy/autophagy pathway. We demonstrated that NLRC5 recruited the E3 ubiquitin ligase CUL2 (cullin 2) to catalyze K48-linked poly-ubiquitination of the NS3 protease domain, which subsequently served as a recognition signal for cargo receptor TOLLIP-mediated selective autophagic degradation. Together, we have demonstrated that NLRC5 exerted an antiviral effect by mediating the degradation of a multifunctional protein of DENV, providing a novel antiviral signal axis of NLRC5-CUL2-NS3-TOLLIP. This study expands our understanding of the regulatory network of NLRC5 in the host defense against virus infection.