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De-ubiquitylation is the most critical step in the ubiquitin-mediated homeostatic control of the NF-κB/IKK basal activity

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Abstract

The role of ubiquitylation in signal-induced activation of nuclear factor -κB (NF-κB) has been well established, while its involvement in maintaining NF-κB basal activity is less certain. Recent evidences demonstrate that in unstimulated cells, NF-κB homeostasis is actually the result of opposing forces: pro-activating activity of the IκB Kinase (IKK) and inhibitory activity of the Inhibitor of -κB (IκB) 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-κB pathway in the absence of extra-cellular stimuli. In contrast, no effects on NF-κB activation were observed upon expression of UbK48R and UbK63R mutants, which are known to impair elongation of Lys48- and Lys63-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-κB activity.

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Funding

This study was supported by COFIN-MIUR PRIN 2006 [prot. 2006058482_001] granted to M. Magnani.

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  1. Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Via A. Saffi, 2, 61029, Urbino, PU, Italy

    Linda Palma, Rita Crinelli, Marzia Bianchi & Mauro Magnani

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  1. Linda Palma
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  2. Rita Crinelli
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Correspondence to Linda Palma.

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Palma, L., Crinelli, R., Bianchi, M. et al. De-ubiquitylation is the most critical step in the ubiquitin-mediated homeostatic control of the NF-κB/IKK basal activity. Mol Cell Biochem 331, 69–80 (2009). https://doi.org/10.1007/s11010-009-0146-x

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