Journal Article

β-TrCP Restricts Lipopolysaccharide (LPS)-Induced Activation of TRAF6-IKK Pathway Upstream of IκBα Signaling

Xu, Jing, Guo, Tingting, Xu, Ying, Zhang, Liting, Liu, Jin, Yuan, Yukang, Zheng, Hui, Wang, Jun, Xiao, Kui

2018

Overview

β transducin repeat-containing protein (β-TrCP) is a Skp1-Cul1-F-box ubiquitin ligase, which plays important roles in controlling numerous signaling pathways. Notably, β-TrCP induces ubiquitination and degradation of inhibitor of NF-κB (IκBα), thus triggering activation of NF-κB signaling. Here, we unexpectedly find that β-TrCP restricts TRAF6-IKK signaling upstream of IκBα induced by lipopolysaccharide (LPS). In LPS-Toll-like receptor 4 (TLR4) pathway, protein kinase D1 (PKD1) is essential for activation of TRAF6-IKK-IκBα signaling including TRAF6 ubiquitination, IKK phosphorylation and subsequent IκBα degradation. We found that LPS promotes binding of β-TrCP to PKD1, and results in downregulation of PKD1 and recovery of IκBα protein level. Knockdown of β-TrCP blocks LPS-induced downregulation of PKD1. Supplement of enough PKD1 in cells inhibits recovery of IκBα protein levels during LPS stimulation. Furthermore, we demonstrate that β-TrCP inhibits LPS-induced TRAF6 ubiquitination and IKK phosphorylation. Taken together, our findings identify β-TrCP as an important negative regulator for upstream signaling of IκBα in LPS pathway, and therefore renew the understanding of the roles of β-TrCP in regulating TLRs inflammatory signaling.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Antibodies / beta-Transducin Repeat-Containing Proteins - genetics / beta-Transducin Repeat-Containing Proteins - immunology / beta-Transducin Repeat-Containing Proteins - metabolism / Down-regulation / E3 ligase / Enzymes / Gene Knockdown Techniques / HEK293 Cells / Humans / I-kappa B Kinase - metabolism / Immunology / Inflammation - immunology / Kinases / Lipopolysaccharides / Lipopolysaccharides - immunology / LPS / Mice / NF-KappaB Inhibitor alpha - immunology / NF-KappaB Inhibitor alpha - metabolism / NF-κB protein / Phosphorylation / Plasmids / protein kinase D1 / Proteins / RAW 264.7 Cells / Signal transduction / Signal Transduction - immunology / TLR4 protein / TNF Receptor-Associated Factor 6 - immunology / TNF Receptor-Associated Factor 6 - metabolism / Toll-like receptors / TRAF6 protein / Transducin / Ubiquitin-protein ligase / Ubiquitination / Ubiquitination - immunology / β-TrCP