De-ubiquitylation is the most critical step in the ubiquitin-mediated homeostatic control of the NF-kappaB/IKK basal activity.
The role of ubiquitylation in signal-induced activation of nuclear factor -kappaB (NF-kappaB) has been well established, while its involvement in maintaining NF-kappaB basal activity is less certain. Recent evidences demonstrate that in unstimulated cells, NF-kappaB homeostasis is actually the result of opposing forces: pro-activating activity of the IkappaB Kinase (IKK) and inhibitory activity of the Inhibitor of -kappaB (IkappaB) proteins. It is well known that endogenous de-ubiquitylating mechanisms are less effective on Ub motifs containing UbG76A. Here, we show that overexpression of a ubiquitin (Ub) G76A mutant leads to persistent activation of the IKK/NF-kappaB pathway in the absence of extra-cellular stimuli. In contrast, no effects on NF-kappaB activation were observed upon expression of UbK48R and UbK63R mutants, which are known to impair elongation of Lys(48)- and Lys(63)-linked poly-ubiquitin chains, respectively. Overall, these findings indicate that under basal conditions, the rate of de-ubiquitylation, rather than that of substrate ubiquitylation, is critical for the maintenance of appropriate levels of IKK/NF-kappaB activity.
Palma
Linda
L
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Via A. Saffi, 2, 61029, Urbino, PU, Italy. linda.palma@uniurb.it
Crinelli
Rita
R
Bianchi
Marzia
M
Magnani
Mauro
M
D019943:Amino Acid Substitution; D004789:Enzyme Activation; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
D050505:Mutant Proteins; D016328:NF-kappa B; D025801:Ubiquitin; D051550:I-kappa B Kinase