title: WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-kappaB activation pathway.
abstract: Toll-like receptors (TLRs) act as sensors of microbial components and elicit innate immune responses. All TLR signaling pathways activate the nuclear factor-kappaB (NF-kappaB), which controls the expression of inflammatory cytokine genes. Transforming growth factor-beta-activated kinase 1 (TAK1) is a serine/threonine protein kinase that is critically involved in the activation of NF-kappaB by tumor necrosis factor (TNFalpha), interleukin-1beta (IL-1beta) and TLR ligands. In this study, we identified a novel protein, WD40 domain repeat protein 34 (WDR34) as a TAK1-interacting protein in yeast two-hybrid screens. WDR34 interacted with TAK1, TAK1-binding protein 2 (TAB2), TAK1-binding protein 3 (TAB3) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in overexpression and under physiological conditions. Overexpression of WDR34 inhibited IL-1beta-, polyI:C- and lipopolysaccharide (LPS)-induced but not TNFalpha-induced NF-kappaB activation, whereas knockdown of WDR34 by a RNA-interference construct potentiated NF-kappaB activation by these ligands. Our findings suggest that WDR34 is a TAK1-associated inhibitor of the IL-1R/TLR3/TLR4-induced NF-kappaB activation pathway.
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation (Ministry of Education), College of Life Sciences, Peking University, 100871 Beijing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Wang
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Li
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Zhai
authors.forename: Dan-Ying
authors.initials: DY
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014018:Tissue Distribution; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D011070:Poly I-C; D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D000099151:MAP Kinase Kinase Kinase 7; C410585:TAB2 protein, human; C543203:WDR34 protein, human