Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.
Advanced Imaging Core Facility, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.
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.
中心体扩增导致遗传不稳定性，并使细胞易于发生肿瘤转化。多余的中心体触发依赖于 PIDDosome（由 PIDD1、RAIDD 和 Caspase-2 组成的多蛋白复合物）的 p53 稳定，其激活导致 p53 的关键抑制剂 MDM2 的切割。在这里，我们证明 ANKRD26 通过中心粒远端附属蛋白将 PIDD1 募集到成熟的中心体。PIDDosome 依赖性 Caspase-2 激活不仅需要 PIDD1 中心体定位，还需要其自身的蛋白水解。有丝分裂失败后，多余的中心体形成簇，这似乎对于 PIDDosome 的激活是必需的。此外，在 DNA 损伤的情况下，该复合物的激活是由 p53 依赖性 PIDD1 水平升高引起的，而与中心体扩增无关。我们提出，在这两种情况下，ANKRD26 依赖性 PIDD1 浓度在靠近中心体的局部增加都可以促进 PIDDosome 的激活。总之，这些发现为中心体如何通过引发信号级联来影响细胞命运提供了一个范例。
