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The E3 ubiquitin ligase RNF 182 inhibits TLR ‐triggered cytokine production through promoting p65 ubiquitination and degradation
Author(s) -
Cao Yang,
Sun Yan,
Chang Huiying,
Sun Xin,
Yang Shusen
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13583
Subject(s) - ubiquitin ligase , proinflammatory cytokine , innate immune system , ubiquitin , microbiology and biotechnology , downregulation and upregulation , cytokine , inflammation , chemistry , immune system , signal transduction , immunology , biology , biochemistry , gene
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.