title: Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation.
abstract: IL-1 receptor-associated kinase (IRAK) is phosphorylated, ubiquitinated, and degraded upon interleukin-1 (IL-1) stimulation. In this study, we showed that IRAK can be ubiquitinated through both Lys-48- and Lys-63-linked polyubiquitin chains upon IL-1 induction. Pellino 3b is the RING-like motif ubiquitin protein ligase that promotes the Lys-63-linked polyubiquitination on IRAK. Pellino 3b-mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the same ubiquitination site, Lys-134 of IRAK, thereby blocking IL-1-induced IRAK degradation. Importantly, the negative impact of Pellino 3b on IL-1-induced IRAK degradation correlated with the inhibitory effect of Pellino 3b on the IL-1-induced TAK1-dependent pathway, suggesting that a positive role of IRAK degradation in IL-1 induced TAK1 activation. Taken together, our results suggest that Pellino 3b acts as a negative regulator for IL-1 signaling by regulating IRAK degradation through its ubiquitin protein ligase activity.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Wen
authors.initials: W
authors.lastname: Qian
authors.forename: Kirk
authors.initials: K
authors.lastname: Staschke
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
authors.forename: Grace
authors.initials: G
authors.lastname: Cui
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.forename: Mariam
authors.initials: M
authors.lastname: Ehsani
authors.forename: Xiliang
authors.initials: X
authors.lastname: Wang
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Qian
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Raymond
authors.initials: R
authors.lastname: Gilmour
authors.forename: Zhengfan
authors.initials: Z
authors.lastname: Jiang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7