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A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation

Official URL:https://doi.org/10.1016/j.molcel.2010.09.008
PubMed:View item in PubMed
Creators Name:Hinz, M. and Stilmann, M. and Coel Arslan, S. and Khanna, K.K. and Dittmar, G. and Scheidereit, C.
Journal Title:Molecular Cell
Journal Abbreviation:Mol Cell
Page Range:63-74
Date:8 October 2010
Keywords:Signal Transducing Adaptor Proteins, Calcium, Cell Cycle Proteins, Cell Nucleus, Cytosol, Double-Stranded DNA Breaks, DNA Damage, DNA-Binding Proteins, Hela Cells, Hep G2 Cells, I-kappa B Kinase, Inhibitor of Apoptosis Proteins, MAP Kinase Kinase Kinases, Mutation, NF-kappa B, Phosphorylation, Poly(ADP-ribose) Polymerases, Protein Binding, Protein Transport, Protein-Serine-Threonine Kinases, RNA Interference, Recombinant Proteins, Signal Transduction, TNF Receptor-Associated Factor 6, Time Factors, Transfection, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitination
Abstract:As part of the genotoxic stress response, cells activate the transcription factor NF-kappaB. The DNA strand break sensor poly(ADP-ribose)-polymerase-1 (PARP-1) and the kinase ataxia telangiectasia mutated (ATM) act as proximal signal mediators. PARP-1 assembles a nucleoplasmic signalosome, which triggers PIASy-mediated IKKgamma SUMOylation. ATM-dependent IKKgamma phosphorylation and subsequent ubiquitination were implicated to activate the cytoplasmic IkappaB kinase (IKK) complex by unknown mechanisms. We show that activated ATM translocates in a calcium-dependent manner to cytosol and membrane fractions. Through a TRAF-binding motif, ATM activates TRAF6, resulting in Ubc13-mediated K63-linked polyubiquitin synthesis and cIAP1 recruitment. The ATM-TRAF6-cIAP1 module stimulates TAB2-dependent TAK1 phosphorylation. Both nuclear PARP-1- and cytoplasmic ATM-driven signaling branches converge at the IKK complex to catalyze monoubiquitination of IKKgamma at K285. Our data indicate that exported SUMOylated IKKgamma acts as a substrate. IKKgamma monoubiquitination is a prerequisite for genotoxic IKK and NF-kappaB activation, but also promotes cytokine signaling.
Publisher:Cell Press (U.S.A.)
Item Type:Article

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