Journal Article

Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new <i>NEMO</i> mutation causing incontinentia pigmenti

Hélène Sebban-Benin, Alessandra Pescatore, Francesca Fusco, Valérie Pascuale, Jérémie Gautheron, Shoji Yamaoka, Anne Moncla, Matilde Valeria Ursini and Gilles Courtois

in Human Molecular Genetics

Volume 16, issue 23, pages 2805-2815
Published in print December 2007 | ISSN: 0964-6906
Published online August 2007 | e-ISSN: 1460-2083 | DOI:
Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti

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The regulatory subunit NEMO is involved in the mechanism of activation of IκB kinase (IKK), the kinase complex that controls the NF-κB signaling pathway. During this process, NEMO is modified post-translationally through K63-linked polyubiquitination. We report the molecular characterization of a new missense mutation of NEMO (A323P) which causes a severe form of incontinentia pigmenti (OMIM#308300), an inherited disease characterized predominantly by skin inflammation. The A323P mutation was found to impair TNF-, IL-1-, LPS- and PMA/ionomycin-induced NF-κB activation, as well as to disrupt TRAF6-dependent NEMO polyubiquitination, due to a defective NEMO/TRAF6 interaction. Mutagenesis identified the affected ubiquitination sites as three lysine residues located in the vicinity of A323. Unexpectedly, these lysines were ubiquitinated together with two previously identified lysines not connected to TRAF6. Mutation of all these ubiquitination sites severely impaired NF-κB activation induced by stimulation with IL-1, LPS, Nod2/RICK or serum/LPA. In contrast, mutation at all of these sites had only a limited effect on stimulation by TNF. These findings indicate that post-translational modification of NEMO through K63-linked polyubiquitination is a key event in IKK activation and that perturbation of this step may cause human pathophysiology.

Journal Article.  6359 words.  Illustrated.

Subjects: Genetics and Genomics

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