title: Cutting Edge: A Cullin-5-TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling.
abstract: TNFR-associated factor (TRAF)6 integrates signals from multiple cell surface receptors for the activation of NF-κB. However, the mechanism underlying LPS-induced TRAF6 signaling remains unclear. We report that cullin-5 (Cul-5), a cullin family scaffold protein, binds to TRAF6 and promotes TRAF6 polyubiquitination at Lys(63) in response to LPS stimulation. A direct interaction between the C-terminal domain of Cul-5 and the TRAF-C domain of TRAF6 facilitates polyubiquitination of TRAF6. Hemizygous Cul-5 knockout is associated with improved survival of mice following LPS challenge and significant delays in the phosphorylation of p65/RelA, ERK, JNK, and p38 MAPKs in LPS-stimulated macrophages, along with a marked decrease in NF-κB activation. These findings identify Cul-5 as a signaling component that connects an LPS-activated TLR4-MyD88 complex to TRAF6 for efficient activation of NF-κB.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; and.
authors.forename: Ziyan
authors.identifier: 0000-0002-5146-2702
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; and.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; and.
authors.forename: Rui
authors.initials: R
authors.lastname: Hao
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; and.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; and richardye@umac.mo sunlei_vicky@sjtu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; and Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China richardye@umac.mo sunlei_vicky@sjtu.edu.cn.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
mesh_terms: D000818:Animals; D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C496871:CUL5 protein, human; D044842:Cullin Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases