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

Item Type:	Article
Title:	A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation
Creators Name:	Hinz, M. and Stilmann, M. and Coel Arslan, S. and Khanna, K.K. and Dittmar, G. and Scheidereit, C.
Abstract:	As part of the genotoxic stress response, cells activate the transcription factor NF-κB. 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 IKKγ SUMOylation. ATM-dependent IKKγ phosphorylation and subsequent ubiquitination were implicated to activate the cytoplasmic IκB 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 IKKγ at K285. Our data indicate that exported SUMOylated IKKγ acts as a substrate. IKKγ monoubiquitination is a prerequisite for genotoxic IKK and NF-κB activation, but also promotes cytokine signaling.
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, IκB Kinase, Inhibitor of Apoptosis Proteins, MAP Kinase Kinase Kinases, Mutation, NF-κB, 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-α, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitination
Source:	Molecular Cell
ISSN:	1097-2765
Publisher:	Cell Press
Volume:	40
Number:	1
Page Range:	63-74
Date:	8 October 2010
Official Publication:	https://doi.org/10.1016/j.molcel.2010.09.008
PubMed:	View item in PubMed

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