Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis

• Published in: Nature communications Vol. 12; no. 1; p. 6984
• Main Authors: Uriarte, Maxime, Sen Nkwe, Nadine, Tremblay, Roch, Ahmed, Oumaima, Messmer, Clémence, Mashtalir, Nazar, Barbour, Haithem, Masclef, Louis, Voide, Marion, Viallard, Claire, Daou, Salima, Abdelhadi, Djaileb, Ronato, Daryl, Paydar, Mohammadjavad, Darracq, Anaïs, Boulay, Karine, Desjardins-Lecavalier, Nicolas, Sapieha, Przemyslaw, Masson, Jean-Yves, Sergeev, Mikhail, Kwok, Benjamin H., Hulea, Laura, Mallette, Frédérick A., Milot, Eric, Larrivée, Bruno, Wurtele, Hugo, Affar, El Bachir
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 30-11-2021; Nature Publishing Group; Nature Research; Nature Portfolio
• Subjects: 13/1; 13/2; 14; 14/35; 14/63; 42/89; 631/80/82/23; 631/80/86/2369; Amino Acids; Amino Acids - metabolism; Animals; Apoptosis; Apoptosis - physiology; Assemblies; Autoantigens; Biochemistry, biophysics & molecular biology; Biochemistry, Genetics and Molecular Biology (all); Biochimie, biophysique & biologie moléculaire; Cell Line, Tumor; Cell Nucleus; Cell Nucleus - metabolism; Cell survival; Chemistry (all); Condensates; Deprivation; DNA Repair Enzymes; DNA Repair Enzymes - metabolism; DNA-Binding Proteins; DNA-Binding Proteins - metabolism; Eukaryotic Cells; Exercise; Fibroblasts; Humanities and Social Sciences; Humans; Ki antigen; Life sciences; Liquid phases; Mammalian cells; Mammals; Mice; multidisciplinary; Nuclei (cytology); Nutrients; Organelles; p53 Protein; Phase separation; Physics and Astronomy (all); Proteasome Endopeptidase Complex; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Biosynthesis; Protein synthesis; Proteins; Proteolysis; RAD23B protein, human; Replenishment; Science; Science (multidisciplinary); Sciences du vivant; Starvation; Stress, Physiological; Ubiquitin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27306-4

Eukaryotic cells have evolved highly orchestrated protein catabolic machineries responsible for the timely and selective disposal of proteins and organelles, thereby ensuring amino acid recycling. However, how protein degradation is coordinated with amino acid supply and protein synthesis has remained largely elusive. Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus) and show that these are a common response of mammalian cells to amino acid deprivation. SIPAN undergo fusion events, rapidly exchange proteasome particles with the surrounding milieu and quickly dissolve following amino acid replenishment. We further show that: (i) SIPAN contain K48-conjugated ubiquitin, (ii) proteasome inhibition accelerates SIPAN formation, (iii) deubiquitinase inhibition prevents SIPAN resolution and (iv) RAD23B proteasome shuttling factor is required for SIPAN formation. Finally, SIPAN formation is associated with decreased cell survival and p53-mediated apoptosis, which might contribute to tissue fitness in diverse pathophysiological conditions.
Upon starvation, cells coordinate protein disposal to recycle amino acids, although the role of the proteasome has been unclear. Here, the authors show that in the mammalian nucleus, proteasomes form condensates that dissolve following nutrient replenishment.