Membrane-lipid therapy in operation: the HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts

• Published in: PloS one 2011-12, Vol.6 (12), p.e28818
• Main Authors: Gombos, Imre, Crul, Tim, Piotto, Stefano, Güngör, Burcin, Török, Zsolt, Balogh, Gábor, Péter, Mária, Slotte, J Peter, Campana, Federica, Pilbat, Ana-Maria, Hunya, Akos, Tóth, Noémi, Literati-Nagy, Zsuzsanna, Vígh, Jr, László, Glatz, Attila, Brameshuber, Mario, Schütz, Gerhard J, Hevener, Andrea, Febbraio, Mark A, Horváth, Ibolya, Vígh, László
• Format: Article
• Language: English
• Subjects: Acetylation; Acetylation - drug effects; Aging; Analgesics; Animals; Apoptosis; Applied physics; beta-Cyclodextrins - pharmacology; Biochemistry; Biology; Cell membranes; Cellular signal transduction; CHO Cells; Cholesterol; Cholesterol - metabolism; Cricetinae; Cricetulus; Diabetes; Disintegration; Drugs; Fever; Fluorescence; Fluorescence microscopy; Gene Expression Regulation - drug effects; Glycosylphosphatidylinositol; Green fluorescent protein; Green Fluorescent Proteins - metabolism; Health aspects; Heat shock factors; Heat shock proteins; Heat stress; Heat tolerance; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Heat-Shock Response - drug effects; HEK293 Cells; HSF1 protein; Humans; Hydroxylamines; In vivo methods and tests; Ischemia; Labeling; Lipid monolayers; Lipid rafts; Lipids; Melanoma; Melanoma - metabolism; Melanoma - pathology; Membrane Lipids - therapeutic use; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Membranes; Mice; Molecular dynamics; Molecular Dynamics Simulation; Molecular machines; Monomolecular films; Nanostructures - chemistry; Oximes - pharmacology; Pharmaceuticals; Piperidines - pharmacology; Platforms; Priming; Protein folding; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Rafts; Rodents; Side effects; Signal transduction; Signal Transduction - drug effects; Signaling; Simulation; Sterols; Stress response; Stress, Physiological - drug effects; Switches; Temperature; Therapy; Trends
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028818

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.