Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway

EMBO J. 2007 Jan 10;26(1):197-208. doi: 10.1038/sj.emboj.7601473. Epub 2006 Dec 7.


Upon DNA damage, a complex called the PIDDosome is formed and either signals NF-kappaB activation and thus cell survival or alternatively triggers caspase-2 activation and apoptosis. PIDD (p53-induced protein with a death domain) is constitutively processed giving rise to a 48-kDa N-terminal fragment containing the leucine-rich repeats (LRRs, PIDD-N) and a 51-kDa C-terminal fragment containing the death domain (DD, PIDD-C). The latter undergoes further cleavage resulting in a 37-kDa fragment (PIDD-CC). Here we show that processing occurs at S446 (generating PIDD-C) and S588 (generating PIDD-CC) by an auto-processing mechanism similar to that found in the nuclear pore protein Nup98/96 and inteins. Auto-cleavage of PIDD determines the outcome of the downstream signaling events. Whereas initially formed PIDD-C mediates the activation of NF-kappaB via the recruitment of RIP1 and NEMO, subsequent formation of PIDD-CC causes caspase-2 activation and thus cell death. A non-cleavable PIDD mutant is unable to translocate from the cytoplasm to the nucleus and loses both activities. In this way, auto-proteolysis of PIDD might participate in the orchestration of the DNA damage-induced life and death signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis
  • Carrier Proteins / chemistry*
  • Carrier Proteins / physiology*
  • Caspase 2 / chemistry*
  • Caspase 2 / metabolism
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • DNA Damage
  • Death Domain Receptor Signaling Adaptor Proteins
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • NF-kappa B / chemistry*
  • NF-kappa B / metabolism
  • Signal Transduction


  • Carrier Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • NF-kappa B
  • PIDD1 protein, human
  • Caspase 2