TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms

Tripartite motif (TRIM) 38 is an E3 ubiquitin ligase that was reported to regulate signaling in innate immune and inflammatory responses in certain cell lines. In this study, we show that Trim38 deficiency markedly increased TLR3- and TLR4-mediated induction of type I IFNs and proinflammatory cytokines, such as TNF-alpha, IL-1 beta, and IL-6, in immune cells and in vivo. Trim38 deficiency also caused the mice to be more susceptible to death triggered by polyinosinic-polycytidylic acid, LPS, and Salmonella typhimurium. Mechanistically, TRIM38 catalyzed K48-linked polyubiquitination of the TLR3/4 adapter protein TIR domain-containing adapter-inducing IFN-beta at K228 and promoted its proteasomal degradation in immune cells. Moreover, Trim38 was highly induced by type I IFNs, which then negatively regulated TNF-alpha/IL-1 beta signaling in IFN-beta-primed immune cells, but not unprimed immune cells, by mediating degradation of Tab2 in a lysosomal-dependent process. These results suggest that Trim38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. This study increases our understanding of how the innate immune response is initiated during the early phase of infection to defend against microbial invasion and is efficiently terminated during the late phase to prevent excessive and harmful inflammatory responses.