Aneuploidy-induced cellular stresses limit autophagic degradation
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...
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2016
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| Online Access: | http://hdl.handle.net/1721.1/102257 https://orcid.org/0000-0002-1501-6190 https://orcid.org/0000-0001-9837-0314 |
| _version_ | 1811084778912350208 |
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| author | Santaguida, Stefano Vasile, Eliza White, Eileen Amon, Angelika B |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Santaguida, Stefano Vasile, Eliza White, Eileen Amon, Angelika B |
| author_sort | Santaguida, Stefano |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:57:28Z |
| format | Article |
| id | mit-1721.1/102257 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:57:28Z |
| publishDate | 2016 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/1022572022-10-01T12:07:51Z Aneuploidy-induced cellular stresses limit autophagic degradation Santaguida, Stefano Vasile, Eliza White, Eileen Amon, Angelika B Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Santaguida, Stefano Vasile, Eliza Amon, Angelika B. 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. National Institutes of Health (U.S.) (GM056800) Kathy and Curt Marble Cancer Research Fund American Italian Cancer Foundation European Community. Marie-Curie Research Networks Italian Association for Cancer Research 2016-04-19T15:18:29Z 2016-04-19T15:18:29Z 2015-09 2015-09 Article http://purl.org/eprint/type/JournalArticle 0890-9369 1549-5477 http://hdl.handle.net/1721.1/102257 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. https://orcid.org/0000-0002-1501-6190 https://orcid.org/0000-0001-9837-0314 en_US http://dx.doi.org/10.1101/gad.269118.115 Genes & Development Creative Commons Attribution http://creativecommons.org/licenses/by-nc/4.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | Santaguida, Stefano Vasile, Eliza White, Eileen Amon, Angelika B Aneuploidy-induced cellular stresses limit autophagic degradation |
| title | Aneuploidy-induced cellular stresses limit autophagic degradation |
| title_full | Aneuploidy-induced cellular stresses limit autophagic degradation |
| title_fullStr | Aneuploidy-induced cellular stresses limit autophagic degradation |
| title_full_unstemmed | Aneuploidy-induced cellular stresses limit autophagic degradation |
| title_short | Aneuploidy-induced cellular stresses limit autophagic degradation |
| title_sort | aneuploidy induced cellular stresses limit autophagic degradation |
| url | http://hdl.handle.net/1721.1/102257 https://orcid.org/0000-0002-1501-6190 https://orcid.org/0000-0001-9837-0314 |
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