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

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.