Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization
Open accessAbstract
Heat shock protein 70 (Hsp70) is a potent survival protein whose depletion triggers massive caspase-independent tumor cell death. Here, we show that Hsp70 exerts its prosurvival function by inhibiting lysosomal membrane permeabilization. The cell death induced by Hsp70 depletion was preceded by the release of lysosomal enzymes into the cytosol and inhibited by pharmacological inhibitors of lysosomal cysteine proteases. Accordingly, the Hsp70-mediated protection against various death stimuli in Hsp70-expressing human tumor cells as well as in immortalized Hsp70 transgenic murine fibroblasts occurred at the level of the lysosomal permeabilization. On the contrary, Hsp70 failed to inhibit the cytochrome c–induced, apoptosome-dependent caspase activation in vitro and Fas ligand–induced, caspase-dependent apoptosis in immortalized fibroblasts. Immunoelectron microscopy revealed that endosomal and lysosomal membranes of tumor cells contained Hsp70. Permeabilization of purified endo/lysosomes by digitonin failed to release Hsp70, suggesting that it is physically associated with the membranes. Finally, Hsp70 positive lysosomes displayed increased size and resistance against chemical and physical membrane destabilization. These data identify Hsp70 as the first survival protein that functions by inhibiting the death-associated permeabilization of lysosomes.
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Under physiological conditions, lysosomal membranes can be stabilized by altering lysosomal cholesterol content or boosting endogenous HSP70 activity.
“Moreover, under physiological conditions, lysosomal membranes can be stabilized by altering lysosomal cholesterol content [788] or by boosting endogenous activity of heat shock protein family A (Hsp70) member 1A (HSPA1A; best known as HSP70) [789, 790].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [790]
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- Authors
- Nylandsted, J., Gyrd-Hansen, M., Danielewicz, A., Fehrenbacher, N., Lademann, U., Høyer-Hansen, M., Weber, E., Multhoff, G., Rohde, M., & Jäättelä, M.
- Affiliations
- Danish Cancer Society (DK)
- 1Department of Apoptosis, Institute for Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark
- Martin Luther University Halle-Wittenberg (DE)
- University Hospital Regensburg (DE)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2004-08-16
- Volume
- 200
- Issue
- 4
- Pages
- 425-435
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2211935
- OpenAlex
- W2108205327
- Cited by
- 545
- References
- 42
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 13 · 2023: 20 · 2022: 17 · 2021: 29 · 2020: 20 · 2019: 13 · 2018: 22 · 2017: 23 · 2016: 30 · 2015: 35 · 2014: 33 · 2013: 45 · 2012: 20
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- Funders
- Kræftens Bekæmpelse
- Sundhed og Sygdom, Det Frie Forskningsråd
- European Commission
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- HSP70, lysosomal membrane permeabilization, cell survival, lysosomal cysteine proteases, lysosomal enzyme release, caspase-independent cell death, apoptosis, endosomal membrane, cancer cell death
- MeSH terms
- Animals, Cathepsins, Cell Membrane Permeability, Cell Survival, HeLa Cells, Humans, Lysosomes, Tumor Cells, Cultured, Immunoblotting, Microscopy, Immunoelectron, Apoptosis, HSP70 Heat-Shock Proteins, Caspases, Mice
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