Sequential Modification of NEMO/IKKgamma by SUMO-1 and Ubiquitin Mediates NF-kappaB Activation by Genotoxic Stress

Cell. 2003 Nov 26;115(5):565-76. doi: 10.1016/s0092-8674(03)00895-x.

Abstract

The transcription factor NF-kappaB is critical for setting the cellular sensitivities to apoptotic stimuli, including DNA damaging anticancer agents. Central to NF-kappaB signaling pathways is NEMO/IKKgamma, the regulatory subunit of the cytoplasmic IkappaB kinase (IKK) complex. While NF-kappaB activation by genotoxic stress provides an attractive paradigm for nuclear-to-cytoplasmic signaling pathways, the mechanism by which nuclear DNA damage modulates NEMO to activate cytoplasmic IKK remains unknown. Here, we show that genotoxic stress causes nuclear localization of IKK-unbound NEMO via site-specific SUMO-1 attachment. Surprisingly, this sumoylation step is ATM-independent, but nuclear localization allows subsequent ATM-dependent ubiquitylation of NEMO to ultimately activate IKK in the cytoplasm. Thus, genotoxic stress induces two independent signaling pathways, SUMO-1 modification and ATM activation, which work in concert to sequentially cause nuclear targeting and ubiquitylation of free NEMO to permit the NF-kappaB survival pathway. These SUMO and ubiquitin modification pathways may serve as anticancer drug targets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Amino Acid Sequence / genetics
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / genetics
  • Ataxia Telangiectasia Mutated Proteins
  • COS Cells
  • Cell Cycle Proteins
  • Cytoplasm / genetics
  • Cytoplasm / metabolism
  • DNA Damage / genetics*
  • DNA-Binding Proteins
  • Humans
  • I-kappa B Kinase
  • Lysine / metabolism
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Signal Transduction / genetics
  • Tumor Suppressor Proteins
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NF-kappa B
  • SUMO-1 Protein
  • Tumor Suppressor Proteins
  • Ubiquitin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Lysine