TY - JOUR
T1 - Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NFκB activation
AU - Xiao, Hui
AU - Qian, Wen
AU - Staschke, Kirk
AU - Qian, Youcun
AU - Cui, Grace
AU - Deng, Li
AU - Ehsani, Mariam
AU - Wang, Xiliang
AU - Qian, Yue Wei
AU - Chen, Zhijian J.
AU - Gilmour, Raymond
AU - Jiang, Zhengfan
AU - Li, Xiaoxia
PY - 2008/5/23
Y1 - 2008/5/23
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M706931200
DO - 10.1074/jbc.M706931200
M3 - Article
C2 - 18326498
AN - SCOPUS:47249131204
SN - 0021-9258
VL - 283
SP - 14654
EP - 14664
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 21
ER -