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<p>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 Lys<sub>109</sub> and Lys<sub>110</sub>, 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月13日

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  • 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

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.