Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway.
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.
Tinel
Antoine
A
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Janssens
Sophie
S
Lippens
Saskia
S
Cuenin
Solange
S
Logette
Emmanuelle
E
Jaccard
Bastienne
B
Quadroni
Manfredo
M
Tschopp
Jürg
J
D000595:Amino Acid Sequence; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry* / Q000502:physiology*; D053143:Caspase 2 / Q000737:chemistry* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D016328:NF-kappa B; C485896:PIDD1 protein, human; D053143:Caspase 2