title: Endotoxin Tolerance Inhibits Degradation of Tumor Necrosis Factor Receptor-Associated Factor 3 by Suppressing Pellino 1 Expression and the K48 Ubiquitin Ligase Activity of Cellular Inhibitor of Apoptosis Protein 2.
abstract: Pellino 1 positively regulates Toll-like receptor 4 signaling by regulating tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and is suppressed with the induction of endotoxin tolerance. However, the role of TRAF3 in endotoxin tolerance is largely unknown. In this study, we found that lipopolysaccharide (LPS) stimulation decreased TARF3 protein expression in mouse Kupffer cells (KCs) and liver tissues, whereas endotoxin tolerization abrogated this effect. Degradative TRAF3 K48-linked ubiquitination and the cytoplasmic translocation of the MYD88-associated multiprotein complex were significantly inhibited in tolerized KCs, which led to markedly impaired activation of MYD88-dependent JNK and p38 and downregulation of inflammatory cytokines. TRAF3 ablation failed to induce a fully endotoxin-tolerant state in RAW264.7 cells. Pellino 1 knockdown in Raw264.7 cells did not impair induction of cIAP2 in response to LPS but inhibited the K63-linked ubiquitination of cellular inhibitor of apoptosis protein 2 (cIAP2) and K48-linked ubiquitination of TRAF3 protein. We also found upregulation of Pellino 1 and downregulation of TRAF3 in liver tissues of patients with cholangitis. Our findings reveal a novel mechanism that endotoxin tolerance reprograms mitogen-activated protein kinase signaling by suppressing Pellino 1-mediated K63-linked ubiquitination of cIAP2, K48-linked ubiquitination, and degradation of TRAF3.
authors.affiliation: Department of Hepatobiliary Surgery.
authors.forename: Peizhi
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery.
authors.forename: Yiyin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liao
authors.affiliation: Department of Hepatobiliary Surgery.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Centre for Lipid Research, & Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University.
authors.forename: Xiongzhong
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Department of Hepatobiliary Surgery.
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
mesh_terms: D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002478:Cells, Cultured; D004731:Endotoxins / Q000633:toxicity*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000473:pathology; D008264:Macrophages; D008297:Male; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D059748:Proteolysis; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004731:Endotoxins; D051034:Inhibitor of Apoptosis Proteins; D009687:Nuclear Proteins; D048008:TNF Receptor-Associated Factor 3; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C418046:Peli1 protein, mouse
keywords: Pellino 1; TRAF3; endotoxin tolerance; ubiquitination