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Article
Subject Categories: Proteins | Differentiation & Death
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, 3, Sophie Janssens1, 4, 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

To whom correspondence should be addressed
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

3 Present address: Department of Pathology, Harvard Medical School, 77 avenue Louis Pasteur, Boston, MA 02115, USA
4 Present address: Department of Molecular Biomedical Research, University of Ghent-VIB, Technologiepark 927, 9052 Gent, Belgium

Received 29 June 2006; Accepted 6 November 2006; Published online 7 December 2006.
Abstract
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
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