Abstract
Aging and pathophysiological conditions are linked to membrane changes which modulate membrane-controlled molecular switches, causing dysregulated heat shock protein (HSP) expression. HSP co-inducer hydroxylamines such as BGP-15 provide advanced therapeutic candidates for many diseases since they preferentially affect stressed cells and are unlikely have major side effects. In the present study in vitro molecular dynamic simulation, experiments with lipid monolayers and in vivo ultrasensitive fluorescence microscopy showed that BGP-15 alters the organization of cholesterol-rich membrane domains. Imaging of nanoscopic long-lived platforms using the raft marker glycosylphosphatidylinositol-anchored monomeric green fluorescent protein diffusing in the live Chinese hamster ovary (CHO) cell plasma membrane demonstrated that BGP-15 prevents the transient structural disintegration of rafts induced by fever-type heat stress. Moreover, BGP-15 was able to remodel cholesterol-enriched lipid platforms reminiscent of those observed earlier following non-lethal heat priming or membrane stress, and were shown to be obligate for the generation and transmission of stress signals. BGP-15 activation of HSP expression in B16-F10 mouse melanoma cells involves the Rac1 signaling cascade in accordance with the previous observation that cholesterol affects the targeting of Rac1 to membranes. Finally, in a human embryonic kidney cell line we demonstrate that BGP-15 is able to inhibit the rapid heat shock factor 1 (HSF1) acetylation monitored during the early phase of heat stress, thereby promoting a prolonged duration of HSF1 binding to heat shock elements. Taken together, our results indicate that BGP-15 has the potential to become a new class of pharmaceuticals for use in ‘membrane-lipid therapy’ to combat many various protein-misfolding diseases associated with aging.
Highlights
A hallmark of stressed cells and organisms is the elevated synthesis of the ubiquitous and highly conserved heat shock protein (HSP) molecular chaperones
Hypothesizing that the drug may affect the properties of membranes, by using molecular dynamics (MD) simulations [18] we provided the first evidence on the docking of BGP-15 into model membranes made of sphingomyelin-cholesterol (SM-Chol)
In vivo ‘‘thinning out clusters while conserving the stoichiometry of labeling’’ (TOCCSL) method, which allows imaging of nanoscopic long-lived platforms with raft-like properties diffusing in the live cell plasma membrane [19], we have shown the preservation of raft integrity challenged by mild heat stress in cells pretreated with the HSP co-inducer
Summary
A hallmark of stressed cells and organisms is the elevated synthesis of the ubiquitous and highly conserved heat shock protein (HSP) molecular chaperones. An aberrantly high level of HSPs is characteristic in cancer, and the converse situation applies for aging, type-2 diabetes or neurodegeneration. Understanding those mechanisms whereby mammalian cells can elicit a stress protein response is of key importance and forms the base for the design of new drugs with the ability to modulate the level of a particular HSP [1]. We have recently shown that another HA derivative NG-094 is remarkably effective at alleviating polyQ-dependent paralysis in C. elegans and confers protection against polyQ proteotoxicity even if administered after disease onset, by a mechanism involving HSF1-controlled expression of molecular chaperones [7]. We have demonstrated that the HA derivative BGP-15 improves insulin sensitivity in genetic- or diet-induced obesity [8] while others have demonstrated that it protects against tachypacing-induced contractile dysfunction in a Drosophila model for atrial fibrillation [9]
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