1. E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting and degrading TLR3 in murine cells
- Author
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Zhongfei Ma, Shuo Liu, Minghong Jiang, Xuetao Cao, Xiaoqi Song, and W.H. Wang
- Subjects
Male ,Proteasome Endopeptidase Complex ,Ubiquitin-Protein Ligases ,viruses ,Immunology ,chemical and pharmacologic phenomena ,Article ,Mice ,Protein Domains ,Ubiquitin ,Animals ,Humans ,Immunology and Allergy ,Polyubiquitin ,Receptor ,Innate immune system ,biology ,Chemistry ,Lysine ,Ubiquitination ,virus diseases ,Signal transducing adaptor protein ,hemic and immune systems ,Immunity, Innate ,Toll-Like Receptor 3 ,Ubiquitin ligase ,Cell biology ,Mice, Inbred C57BL ,HEK293 Cells ,RAW 264.7 Cells ,Infectious Diseases ,TRIF ,Proteolysis ,TLR3 ,biology.protein ,Female ,IRF3 ,Protein Binding ,Signal Transduction - Abstract
Upon recognition of dsRNA, toll-like receptor 3 (TLR3) recruits the adaptor protein TRIF to activate IRF3 and NF-κB signaling, initiating innate immune responses. The ubiquitination of TLR3 downstream signaling molecules and their roles in the innate response have been discovered; however, whether TLR3 itself is ubiquitinated and then functionally involved remains to be elucidated. By immunoprecipitating TLR3-binding proteins in macrophages, we identified ring finger protein 170 (RNF170) as a TLR3-binding E3 ligase. RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 and promoted the degradation of TLR3 through the proteasome pathway. The genetic ablation of RNF170 selectively augmented TLR3-triggered innate immune responses both in vitro and in vivo. Our results reveal a novel role for RNF170 in selectively inhibiting TLR3-triggered innate immune responses by promoting TLR3 degradation.
- Published
- 2019