EMBO J. 2007 Jan 10;26(1):197-208. Epub 2006 Dec 7.

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

Tinel, A., Janssens, S., Lippens, S., Cuenin, S., Logette, E., Jaccard, B., Quadroni, M., Tschopp, J.,
--- - Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
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.
PMID: 17159900External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD PIDD Link RAIDD Co-immunoprecipitation HEK293 Not specified 588-910 Not specified Not specified 17159900
DD PIDD Link RIP Co-immunoprecipitation HEK293 Not specified 446-910 Not specified Not specified 17159900
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DD PIDD Link RAIDD Caspase cleaved assay Caspase2 activation (PIDDosome) 17159900
DD PIDD Link RIP Kinase assay NF-kB activation 17159900
(Link: click this icon to show interactions only between the two corresponding DDs)