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Cell biology

Stability in times of stress

Damaged lysosomes, the principal degradative organelles, can kill a cell. A stress-induced protein controls lysosome stability, providing a potential target to treat lysosome-related diseases and cancer.

A striking study in this issue (page 549) by Kirkegaard et al.1 provides a working model explaining how heat-shock protein 70 (Hsp70), a 'molecular chaperone' that supports the folding of newly formed polypeptides, also promotes cell survival. Heat-shock proteins (Hsps) have a pivotal role in regulating the life and death of cells. Hsp70 is thought to achieve this in part by inhibiting the breakdown of lysosomes — intracellular vesicles that contain degradative (hydrolytic) enzymes. In their study, Kirkegaard et al. report the mechanisms of Hsp70's lysosome-stabilizing effect and highlight a possible therapeutic target for the treatment of diseases involving lysosomal dysfunction.

Tissières and co-workers2 first discovered Hsps in 1974 as proteins that are induced in the salivary glands of the fruitfly Drosophila melanogaster during heat-induced stress. About a decade later, their function as molecular chaperones was elucidated3. Not only do chaperones support polypeptide folding, they also assist protein transport and prevent protein aggregation. This set of functions suggests that Hsps should be located in the cytosol. Unexpectedly, however, a subpopulation of Hsps was found to associate with specific membrane lipids, and with membrane domains (known as rafts) that are enriched with cholesterol and sphingolipids4. Thus, the recently recognized5 'moonlighting' activities of Hsps in cellular membranes might preserve the structural and functional integrity of membranes under conditions of stress.

Hsp70 has been shown6 to prevent the death of cancer cells by inhibiting the permeabilization of lysosome membranes. This finding prompted Kirkegaard et al.1 to investigate how Hsp70 achieves the membrane-stabilizing effect. The authors reveal that when recombinant Hsp70 is added to cancer cells, it is transported to the lysosome by a process called endocytosis (Fig. 1). At the lysosome, Hsp70 interacts with bis(monoacylglycero)phosphate (BMP) — a membrane-bound, anionic phospholipid that is predominantly localized to the inner lysosomal membrane. The authors' work clearly confirms that it is the pH-dependent (the interiors of lysosomes are highly acidic) and high-affinity BMP–Hsp70 interaction that promotes cell survival.

Figure 1: A protein–lipid interaction stabilizes lysosome membranes.

Heat-shock protein 70 (Hsp70) is expressed in the cell under conditions of stress, when it can function as a molecular chaperone. But it also promotes cell survival, in part by stabilizing the membranes of lysosomes — organelles in cells that contain degradative enzymes. Kirkegaard et al.1 propose the following stabilization mechanism. a, Circulating Hsp70 enters cells by receptor-mediated endocytosis. b, Hsp70 in the cytosol is taken up by vesicles called late endosomes. c, The endosomes transfer Hsp70 to lysosomes. d, In the acidic environment of the lysosome lumen, Hsp70 interacts with bis(monoacylglycero) phosphate (BMP), an anionic phospholipid bound to the inner lysosomal membrane. BMP is a cofactor for the enzyme acid sphingomyelinase (ASM). e, The Hsp70–BMP interaction enhances the association of BMP with ASM, activating the enzyme so that it breaks down the lipid sphingomyelin to form ceramide. The increased production of ceramide in lysosomes protects lysosomal membranes from rupturing. The exact role of ceramide remains to be determined.

Kirkegaard et al.1 also identified the ATPase domain of Hsp70 as a major determinant of this lipid–protein interaction and hence of lysosomal stabilization. They found that a point mutation in the ATPase domain of Hsp70 decreases its binding to BMP and abolishes lysosome stabilization, despite the retention of the Hsp70 structure and its chaperone activity. Interestingly, the authors observed that recombinant Hsc70 and Hsp70-2 (Hsps with amino-acid sequences more than 80% identical to Hsp70 that are also transported to lysosomes by endocytosis) do not interact with BMP or stabilize lysosomal membranes when added to cells. Whether these two proteins are naturally located in lysosomes is not known. In support of their working hypothesis of Hsp70 function, Kirkegaard et al. also found that preventing Hsp70–BMP binding abolishes Hsp70's cytoprotective effect.

So how does Hsp70 stabilize lysosomal membranes? The authors demonstrate that the Hsp70–BMP interaction enhances the association of BMP with acid sphingomyelinase (ASM), an enzyme that breaks down the lipid sphingomyelin. ASM is deficient in the lysosomal storage disorder Niemann–Pick disease (NPD); BMP is a cofactor for ASM. When Kirkegaard et al. engineered cells to overproduce Hsp70, the cells were protected against stress-induced lysosomal damage and had higher ASM activity than did their normal counterparts. Furthermore, the authors found that normal cells in which ASM is depleted, and cells from patients with NPD, are sensitive to lysosomal damage induced by oxidative stress. But when the authors added Hsp70 to these cells, both ASM activity and lysosomal stability were enhanced. Importantly, when they added ASM with or without Hsp70 to cells from patients with NPD, this normalized the size of the lysosomes (which are typically enlarged in the diseased cells).

The above findings bring us a step closer to defining the molecular mechanism of Hsp70-mediated lysosomal membrane stabilization, especially in NPD. But we are still far from a clear understanding of how increased ASM activity could ultimately result in increased lysosomal stability and survival in cancer cells. In particular, the role of ceramide — a compound that accumulates in cells as a result of increased ASM activity — is quite controversial. Ceramide is a common intracellular second messenger in apoptosis (a type of programmed cell death). It specifically binds to and activates a hydrolytic enzyme called cathepsin D, the activity of which requires a decrease in cytosolic pH. Such a drop in pH is a consequence of lysosomal proton efflux, which, in turn, leads to cell death7. The proton efflux is caused by enhanced lysosomal membrane permeabilization; given the potentially fatal outcome of this boost in permeabilization, it is not surprising that cancer cells have developed strategies to counteract it.

In fact, the role of ceramide is even more complicated: ASM-mediated increases in the concentration of lysosomal ceramide facilitate the fusion of lysosomes with other intracellular vesicles and with the cell membrane7, through modification of the conformation of lysosomal membranes. This effect might contribute to the Hsp70-mediated increase in lysosomal stability. Conversely, various apoptotic stimuli induce the translocation of ASM to the outer leaflet of the cell membrane, where ceramide can form lipid microdomains that act as sites for the activation of membrane-associated signalling molecules involved in apoptotic signalling, thus triggering cell death7. Ceramide may therefore have opposing effects on cell survival depending on whether it is produced inside the lysosome or in the cell membrane.

Kirkegaard and colleagues' finding1 that Hsp70 interacts with BMP reveals exciting possibilities for treating lysosomal storage disorders such as NPD by increasing the amount of lysosomal Hsp70. The work also reveals a potential strategy for treating cancer by inhibiting the lysosome-stabilizing effects of Hsp70 in tumour cells, thereby promoting lysosome-dependent autophagic cell death, in which the cell digests itself. (Autophagy has emerged as a key process that is deregulated during carcinogenesis.) So molecules that either inhibit Hsp70-related signalling cascades (such as the PI3K/Akt/GSK pathway, which is linked to upregulated Hsp70 transcription in cancers8), or agents that directly block lysosomal localization of Hsp70, might prove useful in anticancer therapy.

Interestingly, the 'moonlighting' Hsp70 has been found to localize to the cell membrane in certain tumour cells by anchoring to a glycosphingolipid (Gb3) in membrane raft domains9. This renders the tumour cells more susceptible to being killed by the immune system's natural killer cells. When treating cancer using an Hsp70-modification strategy, one therefore faces a dilemma: although high levels of Hsp70 expression might confer protection against apoptosis, they could also trigger tumour-specific immune responses. Presumably, primary tumours need to express sufficient Hsp70 to promote tumour-cell survival, but at low enough levels to escape immune surveillance. It is intriguing that the same Hsp70 that can protect tumour growth might also aid immune responses that cause tumour elimination.

Most anticancer drugs bind to proteins and regulate their activity, but lipid-binding drugs can be used in a new anticancer strategy, termed membrane-lipid therapy10. This approach targets membrane lipids as a means of regulating cell functions that are controlled by proteins associated with those lipids. The BMP–Hsp70 interactions proposed by Kirkegaard et al.1 are potential targets for membrane-lipid therapy: Hsp70 ultimately stabilizes lysosomal membranes by associating with a specific lipid (BMP) at a specific cellular location, which stimulates the activity of an enzyme (ASM). The precise mechanism whereby ASM activation stabilizes lysosomal membrane integrity awaits further experimentation. Nevertheless, the search for novel BPM modulators constitutes a new avenue of investigation for drug discovery.


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Horváth, I., Vígh, L. Stability in times of stress. Nature 463, 436–438 (2010).

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