title: Membrane-lipid therapy in operation: the HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts.
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.
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Gombos
authors.forename: Tim
authors.initials: T
authors.lastname: Crul
authors.forename: Stefano
authors.initials: S
authors.lastname: Piotto
authors.forename: Burcin
authors.initials: B
authors.lastname: Güngör
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Török
authors.forename: Gábor
authors.initials: G
authors.lastname: Balogh
authors.forename: Mária
authors.initials: M
authors.lastname: Péter
authors.forename: J Peter
authors.initials: JP
authors.lastname: Slotte
authors.forename: Federica
authors.initials: F
authors.lastname: Campana
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Pilbat
authors.forename: Akos
authors.initials: A
authors.lastname: Hunya
authors.forename: Noémi
authors.initials: N
authors.lastname: Tóth
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Literati-Nagy
authors.forename: László
authors.initials: L
authors.lastname: Vígh
authors.forename: Attila
authors.initials: A
authors.lastname: Glatz
authors.forename: Mario
authors.initials: M
authors.lastname: Brameshuber
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Schütz
authors.forename: Andrea
authors.initials: A
authors.lastname: Hevener
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Ibolya
authors.initials: I
authors.lastname: Horváth
authors.forename: László
authors.initials: L
authors.lastname: Vígh
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008563:Membrane Lipids / Q000627:therapeutic use*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D056004:Molecular Dynamics Simulation; D049329:Nanostructures / Q000737:chemistry; D010091:Oximes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects*; D013696:Temperature; D047392:beta-Cyclodextrins / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D008563:Membrane Lipids; D010091:Oximes; D010880:Piperidines; D047392:beta-Cyclodextrins; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D020830:rac1 GTP-Binding Protein; C031215:betadex; C405586:BGP 15