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

Maxime Uriarte, Nadine Nkwe, Roch Tremblay, Oumaima Ahmed, Clémence Messmer, Nazar Mashtalir, Haithem Barbour, Louis Masclef, Marion Voide, Claire Viallard, Salima Daou, Djaileb Abdelhadi, Daryl Ronato, Mohammadjavad Paydar, Anaïs Darracq, Karine Boulay, Nicolas Desjardins-Lecavalier, Przemyslaw Sapieha, Jean-Yves Masson, Mikhail Sergeev, Benjamin H. Kwok, Laura Hulea, Frédérick A. Mallette, Eric Milot, Bruno Larrivée, Hugo Wurtele and El Bachir Affar ()
Additional contact information
Maxime Uriarte: University of Montréal
Nadine Nkwe: Maisonneuve-Rosemont Hospital Research Center
Roch Tremblay: Maisonneuve-Rosemont Hospital Research Center
Oumaima Ahmed: Maisonneuve-Rosemont Hospital Research Center
Clémence Messmer: University of Montréal
Nazar Mashtalir: Dana-Farber Cancer Institute and Harvard Medical School
Haithem Barbour: Maisonneuve-Rosemont Hospital Research Center
Louis Masclef: University of Montréal
Marion Voide: Maisonneuve-Rosemont Hospital Research Center
Claire Viallard: Maisonneuve-Rosemont Hospital Research Center
Salima Daou: Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Djaileb Abdelhadi: University of Montréal
Daryl Ronato: Oncology Division
Mohammadjavad Paydar: University of Montréal
Anaïs Darracq: Maisonneuve-Rosemont Hospital Research Center
Karine Boulay: Maisonneuve-Rosemont Hospital Research Center
Nicolas Desjardins-Lecavalier: Maisonneuve-Rosemont Hospital Research Center
Przemyslaw Sapieha: Maisonneuve-Rosemont Hospital Research Center
Jean-Yves Masson: Oncology Division
Mikhail Sergeev: Maisonneuve-Rosemont Hospital Research Center
Benjamin H. Kwok: University of Montréal
Laura Hulea: Maisonneuve-Rosemont Hospital Research Center
Frédérick A. Mallette: Maisonneuve-Rosemont Hospital Research Center
Eric Milot: Maisonneuve-Rosemont Hospital Research Center
Bruno Larrivée: Maisonneuve-Rosemont Hospital Research Center
Hugo Wurtele: Maisonneuve-Rosemont Hospital Research Center
El Bachir Affar: Maisonneuve-Rosemont Hospital Research Center

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27306-4

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