Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise

• Published in: Nature cell biology Vol. 26; no. 10; pp. 1691 - 1699
• Main Authors: Park, So Jung, Son, Sung Min, Barbosa, Antonio Daniel, Wrobel, Lidia, Stamatakou, Eleanna, Squitieri, Ferdinando, Balmus, Gabriel, Rubinsztein, David C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2024; Nature Publishing Group
• Subjects: 631/80/39/2346; 692/699; Active Transport, Cell Nucleus; Autophagy; Biodegradation; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell Nucleus - metabolism; Cytoplasm; Cytoplasm - metabolism; Degradation; Developmental Biology; Humans; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; Huntingtons disease; Lethality; Life Sciences; Lysosomes; Neurodegenerative diseases; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Nuclear pores; Nuclear transport; Null cells; Parkinson's disease; Perturbation; Phagosomes; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein transport; Proteins; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Stem Cells; Yeasts
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-024-01488-7

Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington’s disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions. Park et al. show that cells with impaired autophagy shuttle cytoplasmic proteins to the nucleus for degradation by nuclear proteasomes, revealing synergistic vulnerabilities in diseases where autophagy and nucleocytoplasmic transport are compromised.