Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology
Open accessAbstract
Heat shock protein 70 (Hsp70) is an evolutionarily highly conserved molecular chaperone that promotes the survival of stressed cells by inhibiting lysosomal membrane permeabilization, a hallmark of stress-induced cell death. Clues to its molecular mechanism of action may lay in the recently reported stress- and cancer-associated translocation of a small portion of Hsp70 to the lysosomal compartment. Here we show that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential co-factor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (Trp90Phe), as well as the pharmacological and genetic inhibition of ASM, effectively revert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease (NPD) A and B-severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1) encoding for ASM-is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Taken together, these data open exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.
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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 [789]
Recombinant HSP70 or arimiclomol reverts lysosomal abnormalities in cells and murine models of various lysosomal storage disorders.
“In line with this notion, the administration of recombinant HSP70 or the HSP70-inducing agent arimiclomol reverts lysosomal abnormalities in cellula as well as in murine models of various lysosomal storage disorders [789, 791].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [789]
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- Authors
- Kirkegaard, T., Roth, A. G., Petersen, N. H. T., Mahalka, A. K., Olsen, O. D., Moilanen, I., Zylicz, A., Knudsen, J., Sandhoff, K., Arenz, C., Kinnunen, P. K. J., Nylandsted, J., & Jäättelä, M.
- Affiliations
- Danish Cancer Society (DK)
- Humboldt-Universität zu Berlin (DE)
- University of Helsinki (FI)
- University of Southern Denmark (DK)
- University of Bonn (DE)
- Corresponding author
- Jäättelä, Marja
- ORCID
- Venue
- Nature
- Published
- 2010-01-27
- Volume
- 463
- Issue
- 7280
- Pages
- 549-553
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2030410023
- Cited by
- 519
- References
- 35
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 21 · 2023: 45 · 2022: 21 · 2021: 28 · 2020: 45 · 2019: 32 · 2018: 29 · 2017: 31 · 2016: 32 · 2015: 38 · 2014: 33 · 2013: 36 · 2012: 26
- FWCI
- 25.24
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- HSP70, lysosomal membrane permeabilization, Niemann-Pick disease, acid sphingomyelinase, bis(monoacylglycero)phosphate, anionic phospholipid binding, lysosomal storage disease, sphingomyelin metabolism, lysosomal pH
- MeSH terms
- Cells, Cultured, Humans, Hydrogen-Ion Concentration, Intracellular Membranes, Lysophospholipids, Lysosomes, Niemann-Pick Diseases, Sphingomyelin Phosphodiesterase, HSP70 Heat-Shock Proteins, Cell Line, Tumor, Monoglycerides
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