Wdr34 Is A Novel Tak1-Associated Suppressor Of The Il-1r/Tlr3/Tlr4-Induced Nf-Kappa B Activation Pathway

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-kappa B), 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-kappa B by tumor necrosis factor (TNF alpha), interleukin-1 beta (IL-1 beta) 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-1 beta-, polyI:C- and lipopolysaccharide (LPS)-induced but not TNF alpha-induced NF-kappa B activation, whereas knockdown of WDR34 by a RNA-interference construct potentiated NF-kappa B activation by these ligands. Our findings suggest that WDR34 is a TAK1-associated inhibitor of the IL-1R/TLR3/TLR4-induced NF-kappa B activation pathway.