The E3 ubiquitin ligase RNF182 inhibits TLR-triggered cytokine production through promoting p65 ubiquitination and degradation

The activation of Toll-like receptors (TLRs) leads to proinflammatory cytokine production, which is responsible for activating the innate immune system. Thus, TLR signaling is subject to multilayer regulatory control mechanisms that aim to prevent a protective response from causing injury. In the present study, we report that the E3 ubiquitin Ligase RNF182 is highly expressed in macrophages and is specifically upregulated by TLR stimuli (TLR4, TLR3 and TLR9 agonists). Knockdown of RNF182 selectively amplifies TLR signaling by promoting the production of proinflammatory cytokines but not type I interferons in macrophages. Mechanistically, RNF182 promotes the degradation of p65 via K48-linked ubiquitination, resulting in the inhibition of TLR-triggered innate immune responses. Our findings highlight a feedback-negative mechanism for terminating TLR-induced inflammation and maintaining the immunological balance.

RNF182; TLRs; p65; ubiquitination.