Premium
Autoproteolysis of PIDD marks the bifurcation between pro‐death caspase‐2 and pro‐survival NF‐κB pathway
Author(s) -
Tinel Antoine,
Janssens Sophie,
Lippens Saskia,
Cuenin Solange,
Logette Emmanuelle,
Jaccard Bastienne,
Quadroni Manfredo,
Tschopp Jürg
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601473
Subject(s) - biology , caspase 2 , nf κb , nfkb1 , caspase , caspase 8 , apoptosis , cancer research , genetics , virology , programmed cell death , gene , transcription factor
Upon DNA damage, a complex called the PIDDosome is formed and either signals NF‐κB 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‐κB 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.