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The E3 ubiquitin ligase FBXL18 stabilizes BST2 to promote inflammation in RABV-infected astrocytes

文献类型： 外文期刊

作者： Jie Wang;Jianxiong Guo;Nan Li;Zhongzhong Tu;Siyao Liu;Jiaqi Ma;Xinying Zhang;Hairong Cheng;Zhuo Hao;Ye Feng;Shengnan Lv;Guihua Tai;Yifa Zhou;Jiaqi Fu;Changchun Tu;Yan Liu

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期刊名称： Nature Communications

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年卷期： 2025 年 16 卷 1 期

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收录情况： SCIE（2025版） ; ; Nature Index（2023版）

摘要： Lethal encephalitis caused by rabies virus (RABV) in mammals is known to be associated with the production of several pro-inflammatory cytokines, but the mechanism of such induction remains unclear. In this study, we establish that the laboratory strain CVS-11 infects astrocytes which are the most abundant glial cell population and the dominant source of inflammatory factors in the central nervous system (CNS). A screen identifies the E3 ubiquitin ligase FBXL18 as a critical factor responsible for RABV-induced inflammation. Mechanistically, infection by RABV upregulates FBXL18, which induces K11-type ubiquitination of BST2 on Lys109 and Lys110, two residues that are also ubiquitinated for degradation via K33-type ubiquitination by a yet unknown E3 ligase. FBXL18-mediated ubiquitination stabilizes BST2, leading to hyperphosphorylation of IκBα and excessive NF-κB activation. Knockdown of FBXL18 effectively inhibits IL-6 production and RABV replication in astrocytes and neurons, thereby mitigating the virulence of RABV in mice. Our findings suggest that targeting FBXL18 is a potentially effective strategy for rabies treatment.

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