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

Mol Cell. 2010 Oct 8;40(1):63-74. doi: 10.1016/j.molcel.2010.09.008.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Ataxia Telangiectasia Mutated Proteins
  • Calcium / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / enzymology
  • Cytosol / enzymology*
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • MAP Kinase Kinase Kinases / metabolism
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Time Factors
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • Recombinant Proteins
  • TAB2 protein, human
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Ubiquitin
  • UBE2N protein, human
  • Ubiquitin-Conjugating Enzymes
  • BIRC2 protein, human
  • Ubiquitin-Protein Ligases
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Calcium