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?-TrCP Restricts Lipopolysaccharide (LPS)-Induced Activation of TRAF6-IKK Pathway Upstream of I?B? Signaling.

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

SUBMITTER: Liu J 

PROVIDER: S-EPMC6300488 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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

Liu Jin J   Yuan Yukang Y   Xu Jing J   Xiao Kui K   Xu Ying Y   Guo Tingting T   Zhang Liting L   Wang Jun J   Zheng Hui H  

Frontiers in immunology 20181213

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  ...[more]