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.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Calcium / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Nucleus / enzymology
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Cytosol / enzymology*
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DNA Breaks, Double-Stranded
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DNA Damage*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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HeLa Cells
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Hep G2 Cells
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Humans
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I-kappa B Kinase / metabolism
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism*
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MAP Kinase Kinase Kinases / metabolism
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Mutation
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Phosphorylation
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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RNA Interference
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Recombinant Proteins / metabolism
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Signal Transduction*
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism*
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Time Factors
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Transfection
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / metabolism*
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Ubiquitin-Conjugating Enzymes / metabolism
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Ubiquitin-Protein Ligases
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Ubiquitination
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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DNA-Binding Proteins
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Inhibitor of Apoptosis Proteins
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NF-kappa B
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Recombinant Proteins
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TAB2 protein, human
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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Ubiquitin
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UBE2N protein, human
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Ubiquitin-Conjugating Enzymes
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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I-kappa B Kinase
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Calcium