{"database":"biostudies-other","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["9"],"submitter":["Liu J"],"journal":["Frontiers in immunology"],"pagination":["2930"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6300488"],"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."],"repository":["biostudies-other"],"pmcid":["PMC6300488"],"data_source":["Europe PMC"],"pubmed_authors":["Liu J","Zheng H","Xiao K","Guo T","Zhang L","Wang J","Xu J","Yuan Y","Xu Y"],"additional_accession":[]},"is_claimable":false,"name":"?-TrCP Restricts Lipopolysaccharide (LPS)-Induced Activation of TRAF6-IKK Pathway Upstream of I?B? Signaling.","description":"? 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.","dates":{"release":"2018-01-01T00:00:00Z","publication":"2018 ","modification":"2019-03-26T22:35:42Z","creation":"2019-03-26T22:35:42Z"},"accession":"S-EPMC6300488","cross_references":{"eva":["rs8"],"pubmed":["30619291"],"doi":["10.3389/fimmu.2018.02930 "]}}