Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid–liquid phase separation

• Published in: Nature structural & molecular biology Vol. 29; no. 10; pp. 1024 - 1036
• Main Authors: González-Arzola, Katiuska, Díaz-Quintana, Antonio, Bernardo-García, Noelia, Martínez-Fábregas, Jonathan, Rivero-Rodríguez, Francisco, Casado-Combreras, Miguel Á, Elena-Real, Carlos A, Velázquez-Cruz, Alejandro, Gil-Caballero, Sergio, Velázquez-Campoy, Adrián, Szulc, Elzbieta, Gavilán, María P, Ayala, Isabel, Arranz, Rocío, Ríos, Rosa M, Salvatella, Xavier, Valpuesta, José M, Hermoso, Juan A, De la Rosa, Miguel A, Díaz-Moreno, Irene
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.10.2022
• Subjects: Arginine; Biochemistry, Molecular Biology; Caspase; Caspases; Cytochrome; Cytochrome c; Cytochromes; Cytochromes c; Damage; Deoxyribonucleic acid; DNA; DNA damage; Life Sciences; Liquid phases; Localization; Lysine; Mitochondria; Nuclear Proteins; Nuclei (cytology); Nucleoli; Nucleophosmin; Phase separation; Protein transport; Proteins; Spatial discrimination; Structural Biology; Translocation; Tumor suppressor genes; Tumor Suppressor Proteins; Tumors
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-022-00842-3

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.The tumor suppressor ARF is retained by nucleophosmin (NPM) in nucleoli, but shifted out upon DNA damage. In this study, the authors show that cytochrome c triggers a conformational change on NPM, driving ARF release and controlling protein trafficking.