Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology.
NF-kappaB Essential MOdulator (NEMO) has been shown to play a critical role in NF-kappaB activation, as the regulatory subunit of IkappaB 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-1beta signaling. In contrast, activation of NF-kappaB by TNF-alpha was not affected. These data demonstrate that NEMO/TRAF6 interaction has physiological relevance and might represent a new target for therapeutic purposes.
INSERM U781, Hôpital Necker-Enfants Malades and Université Paris-Descartes, 75015 Paris, France.
Jérémie
J
Gautheron
Alessandra
A
Pescatore
Francesca
F
Fusco
Elio
E
Esposito
Shoji
S
Yamaoka
Fabrice
F
Agou
Matilde Valeria
MV
Ursini
Gilles
G
Courtois
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D007184:Incontinentia Pigmenti / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism
C491731:IKBKG protein, human; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D048029:TNF Receptor-Associated Factor 6; D051550:I-kappa B Kinase