PIDD mediates NF-kappaB activation in response to DNA damage

Cell. 2005 Dec 16;123(6):1079-92. doi: 10.1016/j.cell.2005.09.036.

Abstract

Activation of NF-kappaB following genotoxic stress allows time for DNA-damage repair and ensures cell survival accounting for acquired chemoresistance, an impediment to effective cancer therapy. Despite this clinical relevance, little is known about pathways that enable genotoxic-stress-induced NF-kappaB induction. Previously, we reported a role for the p53-inducible death-domain-containing protein, PIDD, in caspase-2 activation and apoptosis in response to DNA damage. We now demonstrate that PIDD plays a critical role in DNA-damage-induced NF-kappaB activation. Upon genotoxic stress, a complex between PIDD, the kinase RIP1, and a component of the NF-kappaB-activating kinase complex, NEMO, is formed. PIDD expression enhances genotoxic-stress-induced NF-kappaB activation through augmented sumoylation and ubiquitination of NEMO. Depletion of PIDD and RIP1, but not caspase-2, abrogates DNA-damage-induced NEMO modification and NF-kappaB activation. We propose that PIDD acts as a molecular switch, controlling the balance between life and death upon DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Binding, Competitive
  • CRADD Signaling Adaptor Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Caspase 2
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage / physiology*
  • Death Domain Receptor Signaling Adaptor Proteins
  • Doxorubicin / pharmacology
  • Etoposide / pharmacology
  • Fatty Acids, Unsaturated / pharmacology
  • HeLa Cells
  • Humans
  • Hypotonic Solutions / pharmacology
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Jurkat Cells
  • Models, Biological
  • NF-kappa B / metabolism*
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Transport / drug effects
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitin / metabolism
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • AGFG1 protein, human
  • Adaptor Proteins, Signal Transducing
  • BCL2L1 protein, human
  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • Carrier Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Fatty Acids, Unsaturated
  • Hypotonic Solutions
  • I-kappa B Proteins
  • IKBKG protein, human
  • NF-kappa B
  • Nuclear Pore Complex Proteins
  • PIDD1 protein, human
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Tumor Necrosis Factor-alpha
  • Ubiquitin
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • bcl-X Protein
  • Etoposide
  • Doxorubicin
  • DNA
  • I-kappa B Kinase
  • Caspase 2
  • Caspases
  • leptomycin B