p53-induced death domain protein 1 (PIDD1)

p53-induced death domain protein 1 (PIDD1) is a stress-inducible scaffold protein regulated by p53, characterized by an N-terminal leucine-rich repeat (LRR) region, two ZU5 domains, a UPA domain, and a C-terminal death domain (DD). It undergoes autoproteolytic cleavage to produce fragments (PIDD-N, PIDD-C, PIDD-CC), which dictate its signaling outcomes. The primary functional role of PIDD1 involves nucleation of multiprotein complexes such as the PIDDosome, either (a) activating caspase-2 and promoting apoptosis (via RAIDD/CRADD) or (b) activating NF-κB survival signaling (via RIPK1 and NEMO). PIDD1 is also implicated in promoting cell cycle arrest, centrosome number surveillance, and translesion DNA synthesis during genotoxic stress. Although not currently targeted by any approved drugs, it is feasible as a future therapeutic target for cancer or inflammatory diseases due to its integrator role in cell stress responses. There are no known small molecule drugs specifically targeting PIDD1, and its safety profile remains theoretical due to the essential roles PIDD1 plays in basic cellular processes.

Other names

Leucine-rich repeat and death domain-containing proteinLRDDPIDDPIDD-NPIDD-CPIDD-CCMGC16925DKFZp434D229MRT75p53-induced death domain-containing protein 1p53-induced protein with a death domain

Potential drug mechanisms could include modulation of PIDDosome formation (e.g., inhibition or stabilization of PIDD1-RAIDD-Caspase-2 complex); Modulation of autoproteolytic processing; Inhibition of PIDD1-dependent NF-κB activation