title: TNFalpha- and IKKbeta-mediated TANK/I-TRAF phosphorylation: implications for interaction with NEMO/IKKgamma and NF-kappaB activation.
abstract: 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.
authors.affiliation: Laboratory of Medical Chemistry and Human Genetics, Center for Biomedical Integrated Genoproteomics, University of Liege, Sart-Tilman, B-4000 Liege, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Bonif
authors.forename: Marie-Alice
authors.initials: MA
authors.lastname: Meuwis
authors.forename: Pierre
authors.initials: P
authors.lastname: Close
authors.forename: Valérie
authors.initials: V
authors.lastname: Benoit
authors.forename: Karen
authors.initials: K
authors.lastname: Heyninck
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Chapelle
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Merville
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
mesh_terms: 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
chemical_list: 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