TRIM31 attenuates microglia-mediated neuroinflammation via targeting TAK1 in vitro and in vivo

Neuroinflammation represents a central pathogenic driver in a spectrum of central nervous system disorders, predominantly mediated by microglial activation and the ensuing release of inflammatory cytokines. While the E3 ubiquitin ligase TRIM31 is implicated in peripheral immunity, its precise function within neuroinflammation defies precise delineation. In this study, we define the role of TRIM31 in microglia-driven neuroinflammation and clarify its molecular mechanism. Utilizing both cellular and murine models of lipopolysaccharide-induced neuroinflammation, we detected a marked induction of TRIM31 expression with LPS stimulation. Genetic knockdown of TRIM31 exacerbated the LPS-triggered upregulation of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β. Conversely, TRIM31 overexpression potently suppressed cytokines release and attenuated neuroinflammatory responses in vitro and in vivo. Mechanistic investigations combining transcriptomic profiling and immunoblotting manifested that TRIM31 directly interacts with TAK1, catalyzing its K48-linked polyubiquitination and subsequent proteasomal degradation. This action provokes the downregulation of the NF-κB activation cascade. Collectively, our findings identify TRIM31 as a critical negative regulator of neuroinflammation and underscore its therapeutic potential for treating neuroinflammatory diseases via targeted degradation of TAK1.