Membrane-lipid therapy in operation

The HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts

I. Gombos, Tim Crul, Stefano Piotto, Burcin Güngör, Z. Török, G. Balogh, Mária Péter, J. Peter Slotte, Federica Campana, Ana Maria Pilbat, Ákos Hunya, Noémi Tóth, Zsuzsanna Literati-Nagy, László Vígh, A. Glatz, Mario Brameshuber, Gerhard J. Schütz, Andrea Hevener, Mark A. Febbraio, I. Horváth & 1 others L. Vígh

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish
Article numbere28818
JournalPLoS One
Volume6
Issue number12
DOIs
Publication statusPublished - 2011

Fingerprint

Signal transduction
Cell membranes
Membrane Lipids
Heat-Shock Proteins
heat shock proteins
heat stress
signal transduction
Signal Transduction
plasma membrane
Cell Membrane
Hot Temperature
therapeutics
lipids
Membranes
cholesterol
Shock
Cholesterol
protein synthesis
Therapeutics
molecular dynamics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Membrane-lipid therapy in operation : The HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts. / Gombos, I.; Crul, Tim; Piotto, Stefano; Güngör, Burcin; Török, Z.; Balogh, G.; Péter, Mária; Slotte, J. Peter; Campana, Federica; Pilbat, Ana Maria; Hunya, Ákos; Tóth, Noémi; Literati-Nagy, Zsuzsanna; Vígh, László; Glatz, A.; Brameshuber, Mario; Schütz, Gerhard J.; Hevener, Andrea; Febbraio, Mark A.; Horváth, I.; Vígh, L.

In: PLoS One, Vol. 6, No. 12, e28818, 2011.

Research output: Contribution to journalArticle

Gombos, I, Crul, T, Piotto, S, Güngör, B, Török, Z, Balogh, G, Péter, M, Slotte, JP, Campana, F, Pilbat, AM, Hunya, Á, Tóth, N, Literati-Nagy, Z, Vígh, L, Glatz, A, Brameshuber, M, Schütz, GJ, Hevener, A, Febbraio, MA, Horváth, I & Vígh, L 2011, 'Membrane-lipid therapy in operation: The HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts', PLoS One, vol. 6, no. 12, e28818. https://doi.org/10.1371/journal.pone.0028818
Gombos, I. ; Crul, Tim ; Piotto, Stefano ; Güngör, Burcin ; Török, Z. ; Balogh, G. ; Péter, Mária ; Slotte, J. Peter ; Campana, Federica ; Pilbat, Ana Maria ; Hunya, Ákos ; Tóth, Noémi ; Literati-Nagy, Zsuzsanna ; Vígh, László ; Glatz, A. ; Brameshuber, Mario ; Schütz, Gerhard J. ; Hevener, Andrea ; Febbraio, Mark A. ; Horváth, I. ; Vígh, L. / Membrane-lipid therapy in operation : The HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts. In: PLoS One. 2011 ; Vol. 6, No. 12.
@article{813afc2a778640c3aa0fe93693747c67,
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.",
author = "I. Gombos and Tim Crul and Stefano Piotto and Burcin G{\"u}ng{\"o}r and Z. T{\"o}r{\"o}k and G. Balogh and M{\'a}ria P{\'e}ter and Slotte, {J. Peter} and Federica Campana and Pilbat, {Ana Maria} and {\'A}kos Hunya and No{\'e}mi T{\'o}th and Zsuzsanna Literati-Nagy and L{\'a}szl{\'o} V{\'i}gh and A. Glatz and Mario Brameshuber and Sch{\"u}tz, {Gerhard J.} and Andrea Hevener and Febbraio, {Mark A.} and I. Horv{\'a}th and L. V{\'i}gh",
year = "2011",
doi = "10.1371/journal.pone.0028818",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Membrane-lipid therapy in operation

T2 - The HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts

AU - Gombos, I.

AU - Crul, Tim

AU - Piotto, Stefano

AU - Güngör, Burcin

AU - Török, Z.

AU - Balogh, G.

AU - Péter, Mária

AU - Slotte, J. Peter

AU - Campana, Federica

AU - Pilbat, Ana Maria

AU - Hunya, Ákos

AU - Tóth, Noémi

AU - Literati-Nagy, Zsuzsanna

AU - Vígh, László

AU - Glatz, A.

AU - Brameshuber, Mario

AU - Schütz, Gerhard J.

AU - Hevener, Andrea

AU - Febbraio, Mark A.

AU - Horváth, I.

AU - Vígh, L.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=83155167596&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83155167596&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0028818

DO - 10.1371/journal.pone.0028818

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e28818

ER -