1. Oncosuppressive functions of PIDD1 in response to centrosome amplification
- Author
-
Ilio Vitale, Gwenola Manic, and Lorenzo Galluzzi
- Subjects
Cancer Research ,Death Domain Receptor Signaling Adaptor Proteins ,Cell division ,Tumour heterogeneity ,Immunology ,Computational biology ,Biology ,Cellular and Molecular Neuroscience ,Text mining ,Humans ,lcsh:QH573-671 ,Centrosome ,business.industry ,lcsh:Cytology ,Comment ,Caspase 2 ,CRADD Signaling Adaptor Protein ,Cell Differentiation ,Cell Biology ,Cysteine Endopeptidases ,HEK293 Cells ,Gene Expression Regulation ,A549 Cells ,Intercellular Signaling Peptides and Proteins ,Tumor Suppressor Protein p53 ,business ,DNA Damage ,Signal Transduction - Abstract
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.
- Published
- 2021