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. Epub 2020 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • CRADD Signaling Adaptor Protein / genetics
  • CRADD Signaling Adaptor Protein / metabolism*
  • Caspase 2 / genetics
  • Caspase 2 / metabolism*
  • Cell Differentiation
  • Centrosome / metabolism*
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • DNA Damage
  • Death Domain Receptor Signaling Adaptor Proteins / genetics
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism*
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • ANKRD26 protein, human
  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • Death Domain Receptor Signaling Adaptor Proteins
  • Intercellular Signaling Peptides and Proteins
  • PIDD1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • CASP2 protein, human
  • Caspase 2
  • Cysteine Endopeptidases