PIDDosome

The PIDDosome is a multiprotein signaling complex that mediates the activation of the caspase-2 protease in response to cellular stress, notably DNA damage and centrosome amplification. Its core components are PIDD (p53-induced protein with a death domain), RAIDD (also called CRADD; a death-domain and CARD-containing adaptor), and procaspase-2. PIDD is transcriptionally upregulated by p53, linking DNA damage signaling to downstream caspase activation.

Mechanism and function: The assembly begins when PIDD binds RAIDD through death-domain interactions, and RAIDD recruits procaspase-2 via CARD–CARD interactions. The proximity of procaspase-2 molecules promotes their autoactivation, generating active caspase-2. Activated caspase-2 can cleave substrates such as MDM2, leading to stabilization of p53, and can initiate apoptotic pathways or influence cell cycle checkpoints. The PIDDosome is thus positioned at the interface between DNA damage responses and cell fate decisions.

Biological significance and context: The PIDDosome is proposed to participate in the cellular surveillance of genotoxic stress and centrosome number, contributing to tumor suppression in certain contexts. However, the requirement for PIDDosome-mediated caspase-2 activation appears to be context-dependent; in some systems caspase-2 activation can occur independently of the PIDDosome, and loss of PIDD or RAIDD often yields variable phenotypes across tissues and stimuli.

Regulation and evolution: Components of the PIDDosome are conserved in vertebrates, with PIDD acting as a p53-inducible sensor that links DNA damage signaling to caspase-2 activation. The precise regulatory mechanisms, including additional interacting partners and post-translational modifications, remain active areas of research.

Clinical relevance: Disruptions in PIDDosome components have been linked to human diseases in several studies, but the clinical significance and mechanisms are still being clarified.

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