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  • The EMBO Journal (2007) 26, 197 - 208
  • doi:10.1038/sj.emboj.7601473

Published online: 7 December 2006

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

Antoine Tinel1,a, Sophie Janssens1,b, Saskia Lippens1, Solange Cuenin1, Emmanuelle Logette1, Bastienne Jaccard1,2, Manfredo Quadroni1,2 and Jürg Tschopp1

  1. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
  2. Protein Analysis Facility, University of Lausanne, Epalinges, Switzerland

Correspondence to:

Jürg Tschopp, Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland. Tel.: +41 21 692 5738; Fax: +41 21 692 6705; E-mail: jurg.tschopp@unil.ch

aPresent address: Department of Pathology, Harvard Medical School, 77 avenue Louis Pasteur, Boston, MA 02115, USA

bPresent address: Department of Molecular Biomedical Research, University of Ghent-VIB, Technologiepark 927, 9052 Gent, Belgium

Received 29 June 2006; Accepted 6 November 2006

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.

  • Keywords:

    • auto-proteolysis,
    • caspase-2,
    • DNA damage,
    • NF-kappaB,
    • PIDD