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Centrosome amplification results into genetic instability and predisposes cells to neoplastic transformation. Supernumerary centrosomes trigger p53 stabilization dependent on the PIDDosome (a multiprotein complex composed by PIDD1, RAIDD and Caspase‐2), whose activation results in cleavage of p53's key inhibitor, MDM2. Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar distal appendage protein ANKRD26. PIDDosome‐dependent Caspase‐2 activation requires not only PIDD1 centrosomal localization, but also its autoproteolysis. Following cytokinesis failure, supernumerary centrosomes form clusters, which appear to be necessary for PIDDosome activation. In addition, in the context of DNA damage, activation of the complex results from a p53‐dependent elevation of PIDD1 levels independently of centrosome amplification. We propose that PIDDosome activation can in both cases be promoted by an ANKRD26‐dependent local increase in PIDD1 concentration close to the centrosome. Collectively, these findings provide a paradigm for how centrosomes can contribute to cell fate determination by igniting a signalling cascade. SYNOPSIS: The PIDDosome is a Caspase‐2‐activating platform assembling in response to two stimuli: genotoxic stress and supernumerary centrosomes. Here, both triggers are shown to rely on centrosomal localization of PIDD1, highlighting the centrosome's capability to influence cell fate. Centriolar distal appendage protein ANKRD26 is the centrosomal PIDD1 receptor.The centrosome recruits the PIDD1 precursor, which undergoes subsequent autoproteolysis.Clustering of PIDD1‐positive extra‐centrosomes is required for PIDDosome activation.P53‐dependent PIDD1 transactivation leads to centrosome‐dependent PIDDosome activation even in the absence of extra‐centrosomes. [ABSTRACT FROM AUTHOR]

The PIDDosome is a Caspase-2-activating platform assembling in response to centrosome amplification or genotoxic stress. We have recently shown that both stimuli depend on ANKRD26 (ankyrin repeat domain-containing protein 26)-mediated localization of PIDD1 (p53-inducible protein with death domain) at the centrosome, demonstrating how this organelle can directly influence cell fate. [ABSTRACT FROM AUTHOR]

The PIDDosome is often used as the alias for a multi-protein complex that includes the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of an endopeptidase belonging to the caspase family, i.e. caspase-2. Yet, PIDD1 variants can also interact with a number of other proteins that include RIPK1 (also known as RIP1) and IKBKG (also known as NEMO), PCNA and RFC5, as well as nucleolar components such as NPM1 or NCL. This promiscuity in protein binding is facilitated mainly by autoprocessing of the full-length protein into various fragments that contain different structural domains. As a result, multiple responses can be mediated by protein complexes that contain a PIDD1 domain. This suggests that PIDD1 acts as an integrator for multiple types of stress that need instant attention. Examples are various types of DNA lesion but also the presence of extra centrosomes that can foster aneuploidy and, ultimately, promote DNA damage. Here, we review the role of PIDD1 in response to DNA damage and also highlight novel functions of PIDD1, such as in centrosome surveillance and scheduled polyploidisation as part of a cellular differentiation program during organogenesis. [ABSTRACT FROM AUTHOR]

The article presents information on possible modes of action, proposed functions and regulation of caspase-2, a member of caspase family that are involved in cell death, inflammation and differentiation. It mentions that after activation, Caspase-2 is able to translocate from cytosol into the nucleus and confirms the hypothesis that it might act as a nuclear protease which orchestrate the response to DNA damage.