Cholesterol promotes clustering of PI(4,5)P2 driving unconventional secretion of FGF2.


Journal

The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356

Informations de publication

Date de publication:
07 11 2022
Historique:
received: 21 06 2021
revised: 22 07 2022
accepted: 30 08 2022
entrez: 29 9 2022
pubmed: 30 9 2022
medline: 4 10 2022
Statut: ppublish

Résumé

FGF2 is a cell survival factor involved in tumor-induced angiogenesis that is secreted through an unconventional secretory pathway based upon direct protein translocation across the plasma membrane. Here, we demonstrate that both PI(4,5)P2-dependent FGF2 recruitment at the inner plasma membrane leaflet and FGF2 membrane translocation into the extracellular space are positively modulated by cholesterol in living cells. We further revealed cholesterol to enhance FGF2 binding to PI(4,5)P2-containing lipid bilayers. Based on extensive atomistic molecular dynamics (MD) simulations and membrane tension experiments, we proposed cholesterol to modulate FGF2 binding to PI(4,5)P2 by (i) increasing head group visibility of PI(4,5)P2 on the membrane surface, (ii) increasing avidity by cholesterol-induced clustering of PI(4,5)P2 molecules triggering FGF2 oligomerization, and (iii) increasing membrane tension facilitating the formation of lipidic membrane pores. Our findings have general implications for phosphoinositide-dependent protein recruitment to membranes and explain the highly selective targeting of FGF2 toward the plasma membrane, the subcellular site of FGF2 membrane translocation during unconventional secretion of FGF2.

Identifiants

pubmed: 36173379
pii: 213511
doi: 10.1083/jcb.202106123
pmc: PMC9526255
pii:
doi:

Substances chimiques

Lipid Bilayers 0
Phosphatidylinositol 4,5-Diphosphate 0
Fibroblast Growth Factor 2 103107-01-3
Cholesterol 97C5T2UQ7J

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Deutsche Forschungsgemeinschaft
ID : SFB/TRR 83
Organisme : Bundesministerium für Bildung und Forschung
Organisme : Max Planck Society
Organisme : Sigrid Juselius Foundation
Organisme : Academy of Finland
Organisme : Human Frontier Science Program
ID : RGP0059/2019
Organisme : Helsinki Institute of Life Science
Organisme : Czech Science Foundation
ID : 19-26854X
Organisme : HPC-EUROPA3
ID : INFRAIA-2016-1-730897
Organisme : H2020 Programme

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022 Lolicato et al.

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Auteurs

Fabio Lolicato (F)

Heidelberg University Biochemistry Center, Heidelberg, Germany.
Department of Physics, University of Helsinki, Helsinki, Finland.

Roberto Saleppico (R)

Heidelberg University Biochemistry Center, Heidelberg, Germany.

Alessandra Griffo (A)

Department of Experimental Physics, Saarland University, Saarbrücken, Germany.
Biophysical Engineering Group, Max Planck Institute for Medical Research, Heidelberg, Germany.

Annalena Meyer (A)

Heidelberg University Biochemistry Center, Heidelberg, Germany.

Federica Scollo (F)

Department of Biophysical Chemistry, J. Heyrovský Institute of Physical Chemistry, Czech Academy of Sciences, Prague, Czech Republic.

Bianca Pokrandt (B)

Heidelberg University Biochemistry Center, Heidelberg, Germany.

Hans-Michael Müller (HM)

Heidelberg University Biochemistry Center, Heidelberg, Germany.

Helge Ewers (H)

Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.

Hendrik Hähl (H)

Department of Experimental Physics, Saarland University, Saarbrücken, Germany.

Jean-Baptiste Fleury (JB)

Department of Experimental Physics, Saarland University, Saarbrücken, Germany.

Ralf Seemann (R)

Department of Experimental Physics, Saarland University, Saarbrücken, Germany.

Martin Hof (M)

Department of Biophysical Chemistry, J. Heyrovský Institute of Physical Chemistry, Czech Academy of Sciences, Prague, Czech Republic.

Britta Brügger (B)

Heidelberg University Biochemistry Center, Heidelberg, Germany.

Karin Jacobs (K)

Department of Experimental Physics, Saarland University, Saarbrücken, Germany.
Max Planck School Matter to Life, Heidelberg, Germany.

Ilpo Vattulainen (I)

Department of Physics, University of Helsinki, Helsinki, Finland.

Walter Nickel (W)

Heidelberg University Biochemistry Center, Heidelberg, Germany.

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