title: β-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to the cytosol for TAK1-dependent NF-κB activation.
abstract: Interleukin-1 (IL-1) receptor-associated kinase (IRAK1) is phosphorylated, ubiquitinated, and degraded upon IL-1 stimulation. IRAK1 can be ubiquitinated through both K48- and K63-linked polyubiquitin chains upon IL-1 stimulation. While the Pellino proteins have been shown to meditate K63-linked polyubiquitination on IRAK1, the E3 ligase for K48-linked ubiquitination of IRAK1 has not been identified. In this study, we report that the SCF (Skp1-Cullin1-F-box)-β-TrCP complex functions as the K48-linked ubiquitination E3 ligase for IRAK1. IL-1 stimulation induced the interaction of IRAK1 with Cullin1 and β-TrCP. Knockdown of β-TrCP1 and β-TrCP2 attenuated the K48-linked ubiquitination and degradation of IRAK1. Importantly, β-TrCP deficiency abolished the translocation TAK1-TRAF6 complex from the membrane to the cytosol, resulting in a diminishment of the IL-1-induced TAK1-dependent pathway. Taken together, these results implicate a positive role of β-TrCP-mediated IRAK1 degradation in IL-1-induced TAK1 activation.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, LSC, Peking University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Nengming
authors.initials: N
authors.lastname: Xiao
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Minjia
authors.initials: M
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D002460:Cell Line; D003600:Cytosol; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology*; D010766:Phosphorylation; D021381:Protein Transport; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051550:I-kappa B Kinase; D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins; D000099151:MAP Kinase Kinase Kinase 7; C471644:BTRC protein, human; C471645:FBXW11 protein, human; C507768:IRAK1 protein, human