Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation.
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.
Xiao
Hui
H
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Qian
Wen
W
Staschke
Kirk
K
Qian
Youcun
Y
Cui
Grace
G
Deng
Li
L
Ehsani
Mariam
M
Wang
Xiliang
X
Qian
Yue-Wei
YW
Chen
Zhijian J
ZJ
Gilmour
Raymond
R
Jiang
Zhengfan
Z
Li
Xiaoxia
X
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
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