biostudies-otherUnknown9Liu JFrontiers in immunology2930https://www.ebi.ac.uk/biostudies/studies/S-EPMC6300488? 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.biostudies-otherPMC6300488Europe PMCLiu JZheng HXiao KGuo TZhang LWang JXu JYuan YXu Yfalse?-TrCP Restricts Lipopolysaccharide (LPS)-Induced Activation of TRAF6-IKK Pathway Upstream of I?B? Signaling.? 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.2018-01-01T00:00:00Z2018 2019-03-26T22:35:42Z2019-03-26T22:35:42ZS-EPMC6300488rs83061929110.3389/fimmu.2018.02930