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TLR-mediated signaling pathways play critical roles in host defense against microbials. However, dysregulation of innate immune and inflammatory responses triggered by TLRs would result in harmful damage to the host. Using a Trim8 gene-knockout mouse model, we show that tripartite motif (TRIM) 8 negatively regulates TLR3- and TLR4-mediated innate immune and inflammatory responses. TRIM8 deficiency leads to increased polyinosinic-polycytidylic acid- and LPS-triggered induction of downstream anti-microbial genes including TNF , Il6 , Rantes , and Ifnb , evaluated serum cytokine levels, and increased susceptibility of mice to polyinosinic-polycytidylic acid- and LPS-induced inflammatory death as well as Salmonella typhimurium infection-induced loss of body weight and septic shock. TRIM8 interacted with Toll/IL-1 receptor domain-containing adapter-inducing IFN-β and mediated its K6- and K33-linked polyubiquitination, leading to disruption of the Toll/IL-1 receptor domain-containing adapter-inducing IFN-β-TANK-binding kinase-1 association. Our findings uncover an additional mechanism on the termination of TLR3/4-mediated inflammatory and innate immune responses.

TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Response by Blocking TRIF–TBK1 Interaction