P53-induced protein with a death domain (PIDD): master of puppets?

Abstract

P53-induced protein with a death domain (PIDD) has been described as primary p53 target gene, induced upon DNA damage. More than 10 years after its discovery, its physiological role in the DNA damage response remains enigmatic, as it seems to be able to execute life-death decisions in vitro, yet genetic ablation in mice failed to reveal an obvious phenotype. Nonetheless, evidence is accumulating that it contributes to the fine-tuning of the DNA-damage response by orchestrating critical processes such as caspase activation or nuclear factor κB translocation and can also exert additional nuclear functions, for example, the modulation of translesion synthesis. In this review, we aim to integrate these observations and propose possible unexplored functions of PIDD.

Figure 1

Generation of PIDD isoforms by splicing or proteolysis. (a) Currently known PIDD isoforms. Isoform 1 contains seven leucine-rich repeat (LRR) domains at the C-terminus followed by two ZU5 domains and an N-terminal DD. In isoform 2, the first 146 amino acids as well as amino acids 580–590 are deleted. Isoform 3 harbors a deletion of amino acids 705–721. Isoform 4 is composed of the two ZU5 and the DD, whereas isoform 5 has not yet been experimentally validated. (b) PIDD processing products. Full length PIDD-FL is processed at S446 to give rise to PIDD-N and PIDD-C. PIDD-C can be further autoproteolytically cleaved at S588, generating PIDD-CC.

Figure 2

Cellular responses reported to engage PIDD. PIDD is induced in response to DNA damage in a p53-dependent manner, and depending on the type and severity of the damage is recruited to different complexes. A low amount of DNA damage leads to autoproteolytical cleavage of full length PIDD to the PIDD-C form. This fragment associates with NEMO and receptor interacting protein (RIP-1), thereby facilitating postranslational modifications on NEMO leading to activation of NFκB. After more severe genotoxic stress, PIDD-C is further autoproteolytically cleaved to the PIDD-CC fragment, which can bind to RAIDD and caspase-2, which is subsequently processed and activated. In response to UV-IR, PIDD-C can displace p21 from proliferating cell nuclear antigen (PCNA), thereby facilitating recruitment of the translesion synthesis repair machinery.