The E3 ubiquitin ligase RNF 182 inhibits TLR ‐triggered cytokine production through promoting p65 ubiquitination and degradation

The activation of Toll‐like receptors ( TLR s) 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 RNF 182 is highly expressed in macrophages and is specifically upregulated by TLR stimuli ( TLR 4, TLR 3 and TLR 9 agonists). Knockdown of RNF 182 selectively amplifies TLR signaling by promoting the production of proinflammatory cytokines but not type I interferons in macrophages. Mechanistically, RNF 182 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.