Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

Abstract Background Lipid species are accurately distributed in the eukaryotic cell so that organelle and plasma membranes have an adequate lipid composition to support numerous cellular functions. In the plasma membrane, a precise regulation of the level of lipids such as phosphatidylserine, PI(4)P...

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Autores principales:	Souade Ikhlef, Nicolas-Frédéric Lipp, Vanessa Delfosse, Nicolas Fuggetta, William Bourguet, Maud Magdeleine, Guillaume Drin
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Lipid transport Phosphatidylserine Phosphoinositide Plasma membrane Kinetics Fluorescence Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5667d2ae829d40f6ab03759713fbc143
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spelling	oai:doaj.org-article:5667d2ae829d40f6ab03759713fbc1432021-11-21T12:42:23ZFunctional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer10.1186/s12915-021-01183-11741-7007https://doaj.org/article/5667d2ae829d40f6ab03759713fbc1432021-11-01T00:00:00Zhttps://doi.org/10.1186/s12915-021-01183-1https://doaj.org/toc/1741-7007Abstract Background Lipid species are accurately distributed in the eukaryotic cell so that organelle and plasma membranes have an adequate lipid composition to support numerous cellular functions. In the plasma membrane, a precise regulation of the level of lipids such as phosphatidylserine, PI(4)P, and PI(4,5)P2, is critical for maintaining the signaling competence of the cell. Several lipid transfer proteins of the ORP/Osh family contribute to this fine-tuning by delivering PS, synthesized in the endoplasmic reticulum, to the plasma membrane in exchange for PI(4)P. To get insights into the role of these PS/PI(4)P exchangers in regulating plasma membrane features, we question how they selectively recognize and transfer lipid ligands with different acyl chains, whether these proteins exchange PS exclusively for PI(4)P or additionally for PI(4,5)P2, and how sterol abundance in the plasma membrane impacts their activity. Results We measured in vitro how the yeast Osh6p and human ORP8 transported PS and PI(4)P subspecies of diverse length and unsaturation degree between membranes by fluorescence-based assays. We established that the exchange activity of Osh6p and ORP8 strongly depends on whether these ligands are saturated or not, and is high with representative cellular PS and PI(4)P subspecies. Unexpectedly, we found that the speed at which these proteins individually transfer lipid ligands between membranes is inversely related to their affinity for them and that high-affinity ligands must be exchanged to be transferred more rapidly. Next we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for exchange processes, because it is a low-affinity ligand, and do not transfer more PS into sterol-rich membranes. Conclusions Our study provides new insights into PS/PI(4)P exchangers by indicating the degree to which they can regulate the acyl chain composition of the PM, and how they control PM phosphoinositide levels. Moreover, we establish general rules on how the activity of lipid transfer proteins relates to their affinity for ligands.Souade IkhlefNicolas-Frédéric LippVanessa DelfosseNicolas FuggettaWilliam BourguetMaud MagdeleineGuillaume DrinBMCarticleLipid transportPhosphatidylserinePhosphoinositidePlasma membraneKineticsFluorescenceBiology (General)QH301-705.5ENBMC Biology, Vol 19, Iss 1, Pp 1-24 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lipid transport Phosphatidylserine Phosphoinositide Plasma membrane Kinetics Fluorescence Biology (General) QH301-705.5
spellingShingle	Lipid transport Phosphatidylserine Phosphoinositide Plasma membrane Kinetics Fluorescence Biology (General) QH301-705.5 Souade Ikhlef Nicolas-Frédéric Lipp Vanessa Delfosse Nicolas Fuggetta William Bourguet Maud Magdeleine Guillaume Drin Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
description	Abstract Background Lipid species are accurately distributed in the eukaryotic cell so that organelle and plasma membranes have an adequate lipid composition to support numerous cellular functions. In the plasma membrane, a precise regulation of the level of lipids such as phosphatidylserine, PI(4)P, and PI(4,5)P2, is critical for maintaining the signaling competence of the cell. Several lipid transfer proteins of the ORP/Osh family contribute to this fine-tuning by delivering PS, synthesized in the endoplasmic reticulum, to the plasma membrane in exchange for PI(4)P. To get insights into the role of these PS/PI(4)P exchangers in regulating plasma membrane features, we question how they selectively recognize and transfer lipid ligands with different acyl chains, whether these proteins exchange PS exclusively for PI(4)P or additionally for PI(4,5)P2, and how sterol abundance in the plasma membrane impacts their activity. Results We measured in vitro how the yeast Osh6p and human ORP8 transported PS and PI(4)P subspecies of diverse length and unsaturation degree between membranes by fluorescence-based assays. We established that the exchange activity of Osh6p and ORP8 strongly depends on whether these ligands are saturated or not, and is high with representative cellular PS and PI(4)P subspecies. Unexpectedly, we found that the speed at which these proteins individually transfer lipid ligands between membranes is inversely related to their affinity for them and that high-affinity ligands must be exchanged to be transferred more rapidly. Next we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for exchange processes, because it is a low-affinity ligand, and do not transfer more PS into sterol-rich membranes. Conclusions Our study provides new insights into PS/PI(4)P exchangers by indicating the degree to which they can regulate the acyl chain composition of the PM, and how they control PM phosphoinositide levels. Moreover, we establish general rules on how the activity of lipid transfer proteins relates to their affinity for ligands.
format	article
author	Souade Ikhlef Nicolas-Frédéric Lipp Vanessa Delfosse Nicolas Fuggetta William Bourguet Maud Magdeleine Guillaume Drin
author_facet	Souade Ikhlef Nicolas-Frédéric Lipp Vanessa Delfosse Nicolas Fuggetta William Bourguet Maud Magdeleine Guillaume Drin
author_sort	Souade Ikhlef
title	Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
title_short	Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
title_full	Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
title_fullStr	Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
title_full_unstemmed	Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
title_sort	functional analyses of phosphatidylserine/pi(4)p exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/5667d2ae829d40f6ab03759713fbc143
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Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts reveal unanticipated rules on lipid transfer

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