TNFalpha- and IKKbeta-mediated TANK/I-TRAF phosphorylation: implications for interaction with NEMO/IKKgamma and NF-kappaB activation.
Pro-inflammatory cytokines trigger signalling cascades leading to NF-kappaB (nuclear factor-kappaB)-dependent gene expression through IKK [IkappaB (inhibitory kappaB) kinase]-dependent phosphorylation and subsequent degradation of the IkappaB proteins and via induced phosphorylation of p65. These signalling pathways rely on sequentially activated kinases which are assembled by essential and non-enzymatic scaffold proteins into functional complexes. Here, we show that the pro-inflammatory cytokine TNFalpha (tumour necrosis factor alpha) promotes TANK [TRAF (TNF receptor-associated factor) family member associated NF-kappaB activator] recruitment to the IKK complex via a newly characterized C-terminal zinc finger. Moreover, we show that TANK is phosphorylated by IKKbeta upon TNFalpha stimulation and that this modification negatively regulates TANK binding to NEMO (NF-kappaB essential modulator). Interestingly, reduced TANK expression by RNA interference attenuates TNFalpha-mediated induction of a subset of NF-kappaB target genes through decreased p65 transactivation potential. Therefore the scaffold protein TANK is required for the cellular response to TNFalpha by connecting upstream signalling molecules to the IKKs and p65, and its subsequent IKKbeta-mediated phosphorylation may be a mechanism to terminate the TANK-dependent wave of NF-kappaB activation.
Bonif
Marianne
M
Laboratory of Medical Chemistry and Human Genetics, Center for Biomedical Integrated Genoproteomics, University of Liege, Sart-Tilman, B-4000 Liege, Belgium.
Meuwis
Marie-Alice
MA
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Pierre
P
Benoit
Valérie
V
Heyninck
Karen
K
Chapelle
Jean-Paul
JP
Bours
Vincent
V
Merville
Marie-Paule
MP
Piette
Jacques
J
Beyaert
Rudi
R
Chariot
Alain
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D016335:Zinc Fingers
D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C484406:TANK protein, human; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase