Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid–liquid phase separation
Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid-liquid phase separation.
2 Université Paris-Saclay
3 INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement
4 IQFR - Instituto de Química Física Rocasolano = Instituto de Química Física Blas Cabrera = Institute of Physical Chemistry Rocasolano
5 IBS - UMR 5075 - Institut de biologie structurale
6 BIFI - Instituto de Biocomputación y Física de Sistemas Complejos = Institute for Biocomputation and Physics of Complex Systems
7 Universidad de Zaragoza = University of Zaragoza [Saragossa University] = Université de Saragosse
8 IIS Aragon - Aragón Health Research Institute - Instituto de Investigacion Sanitaria Aragon
9 CIBERehd - Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas = Biomedical Research Network Center for Liver and Digestive Diseases [Madrid]
10 ARAID - Fundación Agencia Aragonesa para la Investigación y el Desarrollo = Aragonese Foundation for Research & Development
11 IRB - Institute for Research in Biomedicine [Barcelona, Spain]
12 CABIMER - Centro Andaluz de Biología Molecular y Medicina Regenerativa = Andalusian Molecular Biology and Regenerative Medicine Center
13 CNB-CSIC - Centro Nacional de Biotecnología [Madrid]
14 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies
15 CSIC - Consejo Superior de Investigaciones Cientificas [España] = Spanish National Research Council [Spain]
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Résumé
The regular functioning of the nucleolus and nucleus-mitochondria crosstalk are considered unrelated processes, yet cytochrome c (Cc) migrates to the nucleus and even the nucleolus under stress conditions. Nucleolar liquid-liquid phase separation usually serves the cell as a fast, smart mechanism to control the spatial localization and trafficking of nuclear proteins. Actually, the alternative reading frame (ARF), a tumor suppressor protein sequestered by nucleophosmin (NPM) in the nucleoli, is shifted out from NPM upon DNA damage. DNA damage also triggers early translocation of respiratory Cc to nucleus before cytoplasmic caspase activation. Here, we show that Cc can bind to nucleolar NPM by triggering an extended-to-compact conformational change, driving ARF release. Such a NPM-Cc nucleolar interaction can be extended to a general mechanism for DNA damage in which the lysine-rich regions of Cc-rather than the canonical, arginine-rich stretches of membrane-less organelle components-controls the trafficking and availability of nucleolar proteins.