Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction

Minji Kim, Remigiusz A. Serwa, Lukasz Samluk, Ida Suppanz, Agata Kodroń, Tomasz M. Stępkowski, Praveenraj Elancheliyan, Biniyam Tsegaye, Silke Oeljeklaus, Michal Wasilewski, Bettina Warscheid and Agnieszka Chacinska ()
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Minji Kim: IMol Polish Academy of Sciences
Remigiusz A. Serwa: IMol Polish Academy of Sciences
Lukasz Samluk: University of Warsaw
Ida Suppanz: University of Freiburg
Agata Kodroń: IMol Polish Academy of Sciences
Tomasz M. Stępkowski: IMol Polish Academy of Sciences
Praveenraj Elancheliyan: IMol Polish Academy of Sciences
Biniyam Tsegaye: IMol Polish Academy of Sciences
Silke Oeljeklaus: University of Würzburg
Michal Wasilewski: IMol Polish Academy of Sciences
Bettina Warscheid: University of Freiburg
Agnieszka Chacinska: IMol Polish Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.

Date: 2023
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DOI: 10.1038/s41467-023-39642-8

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