title: Keratin 8 limits TLR-triggered inflammatory responses through inhibiting TRAF6 polyubiquitination.
abstract: Toll-like receptors (TLRs) have critical roles in innate immunity and inflammation and the detailed mechanisms by which TLR signaling is fine tuned remain unclear. Keratin 8 (CK8) belongs to the type II keratin family and is the major compontent of the intermediate filaments of simple or single-layered epithelia. Here we report that down-regulation of CK8 in mice enhanced TLR-mediated responses, rendering mice more susceptible to lipopolysaccharide (LPS)-induced endotoxin shock and Escherichia coli-caused septic peritonitis with reduced survival, elevated levels of inflammation cytokines and more severe tissue damage. We found that CK8 suppressed TLR-induced nuclear factor (NF)-κB activation and interacted with the adaptor tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) to prevent its polyubiquitination. Our findings demonstrate a novel role of CK8 in negative regulation of TLR/NF-κB signaling and highlight a previously unidentified nonclassical function for CK8 in limiting inflammatory responses.
authors: Tianjin University, School of Chemical Engineering and Technology, Department of pharmaceutical engineering, Tianjin 300072, China.|State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Xiao-Ming
authors: XM
authors: Dong
authors: AnHui Medical University, Hefei, 230032, China.
authors: En-Dong
authors: ED
authors: Liu
authors: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, 1 Shuai Fu Yuan Hu Tong, Beijing 100730, China.
authors: Yun-Xiao
authors: YX
authors: Meng
authors: AnHui Medical University, Hefei, 230032, China.
authors: Chao
authors: C
authors: Liu
authors: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, 1 Shuai Fu Yuan Hu Tong, Beijing 100730, China.
authors: Ya-Lan
authors: YL
authors: Bi
authors: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, 1 Shuai Fu Yuan Hu Tong, Beijing 100730, China.
authors: Huan-Wen
authors: HW
authors: Wu
authors: Tianjin University, School of Chemical Engineering and Technology, Department of pharmaceutical engineering, Tianjin 300072, China.
authors: Yan-Chao
authors: YC
authors: Jin
authors: AnHui Medical University, Hefei, 230032, China.
authors: Jing-Hui
authors: JH
authors: Yao
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Liu-Jun
authors: LJ
authors: Tang
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Jian
authors: J
authors: Wang
authors: AnHui Medical University, Hefei, 230032, China.
authors: Min
authors: M
authors: Li
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Chao
authors: C
authors: Zhang
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Miao
authors: M
authors: Yu
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Yi-Qun
authors: YQ
authors: Zhan
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Hui
authors: H
authors: Chen
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Chang-Hui
authors: CH
authors: Ge
authors: Tianjin University, School of Chemical Engineering and Technology, Department of pharmaceutical engineering, Tianjin 300072, China.|State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Xiao-Ming
authors: XM
authors: Yang
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.|AnHui Medical University, Hefei, 230032, China.
authors: Chang-Yan
authors: CY
authors: Li
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004731:Endotoxins / Q000633:toxicity; D004927:Escherichia coli Infections / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D053533:Keratin-8 / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010538:Peritonitis / Q000473:pathology; D012772:Shock, Septic / Q000473:pathology*; D016019:Survival Analysis; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D004731:Endotoxins; D053533:Keratin-8; C486595:Krt8 protein, mouse; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors