NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation.
The cytokines TNFalpha and IL-1beta induce inflammation through activation of transcription factors NF-kappaB. TAB2 is an adapter protein that facilitates TNFalpha and IL-1beta-mediated NF-kappaB activation. In this work, using yeast two-hybrid system TAB2 was identified to interact with NUMBL. The interaction was further confirmed in vitro and in vivo. PTB domain of NUMBL and C-terminal region are required for their interaction. Overexpression of NUMBL inhibited TNFalpha, IL-1beta-induced activation of NF-kappaB signaling pathway. NUMBL also inhibited TAB2, TAK1, TRAF6 and RIP-induced activation of NF-kappaB in a dose-dependent manner. We found that NUMBL can impair TAB2 binding to TRAF6 or RIP and inhibit ubiquitination of TRAF6 enhanced by TAB2. Taken together, our data suggest that NUMBL is involved in negative regulation of NF-kappaB signaling through its interaction with TAB2. These findings also reveal the new functions of NUMBL and implicate that NUMBL potentially links Notch pathway to NF-kappaB pathway.
Ma
Qi
Q
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, PR China.
Zhou
Li
L
Shi
Huili
H
Huo
Keke
K
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006367:HeLa Cells; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C530266:NUMBL protein, human; C410585:TAB2 protein, human; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases