Article
- The EMBO Journal (2007) 26, 197 - 208
- doi:10.1038/sj.emboj.7601473
Published online: 7 December 2006
Subject Categories:
Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-
B pathway
Antoine Tinel1,a, Sophie Janssens1,b, Saskia Lippens1, Solange Cuenin1, Emmanuelle Logette1, Bastienne Jaccard1,2, Manfredo Quadroni1,2 and Jürg Tschopp1
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
- 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
Abstract
Upon DNA damage, a complex called the PIDDosome is formed and either signals NF-
B 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-B 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-B,
- PIDD
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