Aneuploidy-induced cellular stresses limit autophagic degradation
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Santaguida-2015-Aneuploidy-induced c.pdf
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Author(s)
Santaguida, Stefano
Vasile, Eliza
White, Eileen
Amon, Angelika B
Date Issued
September 2015
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Santaguida, Stefano, Eliza Vasile, Eileen White, and Angelika Amon. “Aneuploidy-Induced Cellular Stresses Limit Autophagic Degradation.” Genes Dev. 29, no. 19 (September 24, 2015): 2010–2021.
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Final published version
Abstract
An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Aneuploid cells experience a number of stresses that are caused by aneuploidy-induced proteomic changes. How the aneuploidy-associated stresses affect cells and whether cells respond to them are only beginning to be understood. Here we show that autophagosomal cargo such as protein aggregates accumulate within lysosomes in aneuploid cells. This causes a lysosomal stress response. Aneuploid cells activate the transcription factor TFEB, a master regulator of autophagic and lysosomal gene expression, thereby increasing the expression of genes needed for autophagy-mediated protein degradation. Accumulation of autophagic cargo within the lysosome and activation of TFEB-responsive genes are also observed in cells in which proteasome function is inhibited, suggesting that proteotoxic stress causes TFEB activation. Our results reveal a TFEB-mediated lysosomal stress response as a universal feature of the aneuploid state.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1101/gad.269118.115
