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 ...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.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(grant 81788101 to X.C.grant 81871236 to M.J.)the National 135 Mega Program of China(grant 2017ZX10202203-002 to M.J.grant 2017ZX10203206-001 to X.C.)+1 种基金the CAMS Innovation Fund for Medical Sciences(grant 2016-12M-1-003 to X.C.)the Medical Epigenetics Research Center,Chinese Academy of Medical Sciences(2018PT31015).
文摘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.
