Crosstalk between the NF-kappaB activating IKK-complex and the CSN signalosome.
A great variety of signalling pathways regulating inflammation, cell development and cell survival require NF-kappaB transcription factors, which are normally inactive due to binding to inhibitors, such as IkappaBalpha. The canonical activation pathway of NF-kappaB is initiated by phosphorylation of the inhibitor by an IkappaB kinase (IKK) complex triggering ubiquitination of IkappaB molecules by SCF-type E3-ligase complexes and rapid degradation by 26S-proteasomes. The ubiquitination machinery is regulated by the COP9 signalosome (CSN). We show that IkappaB kinases interact with the CSN-complex, as well as the SCF-ubiquitination machinery, providing an explanation for the rapid signalling-induced ubiquitination and degradation of IkappaBalpha. Furthermore, we reveal that IKK's phosphorylate not only IkappaBalpha, but also the CSN-subunit Csn5/JAB1 (c-Jun activation domain binding protein-1) and that IKK2 influences ubiquitination of Csn5/JAB1. Our observations imply that the CSN complex acts as an inhibitor of constitutive NF-kappaB activity in non-activated cells. Knock-down of Csn5/JAB1 clearly enhanced basal NF-kappaB activity and improved cell survival under stress. The inhibitory effect of Csn5/JAB1 requires a functional MPN(+) metalloprotease domain, which is responsible for cleaving ubiquitin-like Nedd8-modifications. Upon activation of cells with tumour necrosis factor-alpha, the CSN complex dissociates from IKK's allowing full and rapid activation of the NF-kappaB pathway by the concerted action of interacting protein complexes.
Orel
Lukas
L
Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical Univ. of Vienna, Austria.
Neumeier
Hannah
H
Hochrainer
Karin
K
Binder
Bernd R
BR
Schmid
Johannes A
JA
D017209:Apoptosis; D000075686:COP9 Signalosome Complex; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D054875:Ubiquitination
D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D051550:I-kappa B Kinase; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex