2. Academic Validation
  3. Centriolar distal appendages activate the centrosome-PIDDosome-p53 signalling axis via ANKRD26

Centriolar distal appendages activate the centrosome-PIDDosome-p53 signalling axis via ANKRD26

  • EMBO J. 2021 Feb 15;40(4):e104844. doi: 10.15252/embj.2020104844.
Matteo Burigotto 1,  Alessia Mattivi 1,  Daniele Migliorati 1,  Giovanni Magnani 1,  Chiara Valentini 1,  Michela Roccuzzo 2,  Martin Offterdinger 3,  Massimo Pizzato 4,  Alexander Schmidt 5,  Andreas Villunger 6 7,  Stefano Maffini 8,  Luca L Fava 1
Affiliations

Affiliations

  • 1 Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.
  • 2 Advanced Imaging Core Facility, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.
  • 3 Division of Neurobiochemistry, Biooptics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 4 Laboratory of Virus-Cell Interaction, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.
  • 5 Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
  • 6 Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 7 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 8 Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
PMID: 33350486 DOI: 10.15252/embj.2020104844
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.

Keywords

PIDDosome; cell cycle; centrosome; p53; proteolysis.

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