Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology

NF-κB Essential MOdulator (NEMO) has been shown to play a critical role in NF-κB activation, as the regulatory subunit of IκB kinase. Upon cell stimulation, NEMO can be modified through phosphorylation, sumoylation or ubiquitination. In the latter case, not much is known regarding the exact function...

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Bibliographic Details
Published in:Human molecular genetics 2010-08, Vol.19 (16), p.3138-3149
Main Authors: Gautheron, Jérémie, Pescatore, Alessandra, Fusco, Francesca, Esposito, Elio, Yamaoka, Shoji, Agou, Fabrice, Ursini, Matilde Valeria, Courtois, Gilles
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Binding Sites
Binding Sites - genetics
Biological and medical sciences
Blotting, Western
Cell Line
Cells, Cultured
Dermatology
Embryo, Mammalian
Embryo, Mammalian - cytology
Fibroblasts
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Humans
I-kappa B Kinase
I-kappa B Kinase - chemistry
I-kappa B Kinase - genetics
I-kappa B Kinase - metabolism
Immunoprecipitation
Incontinentia Pigmenti
Incontinentia Pigmenti - genetics
Incontinentia Pigmenti - metabolism
Incontinentia Pigmenti - pathology
Interleukin-1beta
Interleukin-1beta - pharmacology
Intracellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins - chemistry
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Life Sciences
Medical sciences
Mice
Mice, Knockout
Models, Molecular
Molecular and cellular biology
Mutation
Pigmentary diseases of the skin
Protein Binding
Protein Binding - drug effects
Protein Structure, Tertiary
TNF Receptor-Associated Factor 6
TNF Receptor-Associated Factor 6 - genetics
TNF Receptor-Associated Factor 6 - metabolism
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Summary:NF-κB Essential MOdulator (NEMO) has been shown to play a critical role in NF-κB activation, as the regulatory subunit of IκB kinase. Upon cell stimulation, NEMO can be modified through phosphorylation, sumoylation or ubiquitination. In the latter case, not much is known regarding the exact function of this posttranslational modification. One of the E3 ligase responsible for K63-linked NEMO polyubiquitination is TRAF6, which participates in several signaling pathways controlling immunity, osteoclastogenesis, skin development and brain functions. We previously observed a potentially important interaction between NEMO and TRAF6. In this study, we defined in more detail the domains required for this interaction, uncovering a new binding site for TRAF6 located at the amino-terminus of NEMO and recognized by the coiled-coil domain of TRAF6. This site appears to work in concert with the previously identified NEMO ubiquitin-binding domain which binds polyubiquitinated chains, suggesting a dual mode of TRAF6 recognition. We also showed that E57K mutation of NEMO found in a mild form of the genetic disease incontinentia pigmenti, resulted in impaired TRAF6 binding and IL-1β signaling. In contrast, activation of NF-κB by TNF-α was not affected. These data demonstrate that NEMO/TRAF6 interaction has physiological relevance and might represent a new target for therapeutic purposes.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddq222