Human Molecular Genetics Advance Access originally published online on August 29, 2007
Human Molecular Genetics 2007 16(23):2805-2815; doi:10.1093/hmg/ddm237
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti
,*1 INSERM U697, Pavillon Bazin, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France, 2 Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ (CNR), 80131 Naples, Italy, 3 Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan and 4 Département de Génétique Médicale, Hôpital des Enfants de la Timone, 13385 Marseille, France
* To whom correspondence should be addressed. Tel: +33 153722085; Fax: +33 153722051; E-mail: gilles.courtois{at}stlouis.inserm.fr
Received June 21, 2007; Revised August 18, 2007; Accepted August 21, 2007
The regulatory subunit NEMO is involved in the mechanism of activation of I
B kinase (IKK), the kinase complex that controls the NF-B 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-B 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-B 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.
The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Paz, M. Vilasco, M. Arguello, Q. Sun, J. Lacoste, T. L.-A. Nguyen, T. Zhao, E. A. Shestakova, S. Zaari, A. Bibeau-Poirier, et al. Ubiquitin-Regulated Recruitment of I{kappa}B Kinase {varepsilon} to the MAVS Interferon Signaling Adapter Mol. Cell. Biol., June 15, 2009; 29(12): 3401 - 3412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Keating and A. G. Bowie Role of Non-degradative Ubiquitination in Interleukin-1 and Toll-like Receptor Signaling J. Biol. Chem., March 27, 2009; 284(13): 8211 - 8215. [Full Text] [PDF]
|
|
|
|
 |
|
 H.-S. Jin, D.-H. Lee, D.-H. Kim, J.-H. Chung, S.-J. Lee, and T. H. Lee cIAP1, cIAP2, and XIAP Act Cooperatively via Nonredundant Pathways to Regulate Genotoxic Stress-Induced Nuclear Factor-{kappa}B Activation Cancer Res., March 1, 2009; 69(5): 1782 - 1791. [Abstract] [Full Text] [PDF]
|
|