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Depletion of Plasma Membrane PI4P by ORP5 Requires Hydrolysis by SAC1 in Acceptor Membranes

View ORCID ProfileColleen P. Doyle, Liz Timple, View ORCID ProfileGerald R. V. Hammond
doi: https://doi.org/10.1101/2022.08.04.502856
Colleen P. Doyle
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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Liz Timple
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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Gerald R. V. Hammond
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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  • For correspondence: ghammond@pitt.edu
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Abstract

Oxysterol binding protein (OSBP)-related proteins (ORPs) 5 and 8 have been shown to deplete the lipid phosphatidylinositol 4-phosphate (PI4P) at sites of membrane contact between the endoplasmic reticulum (ER) and plasma membrane (PM). This is believed to be caused by transport of PI4P from the PM to the ER, where PI4P is degraded by an ER-localized SAC1 phosphatase. This is proposed to power the anti-port of phosphatidylserine (PS) lipids from ER to PM, up their concentration gradient. Alternatively, ORPs have been proposed to sequester PI4P, dependent on the concentration of their alternative lipid ligand. Here, we aimed to distinguish these possibilities in living cells by orthogonal targeting of ORP5 to PM-mitochondrial contact sites. We demonstrate that ORP5 is unable to deplete PM PI4P or accumulate the lipid in mitochondrial outer membranes when acting alone, ruling out both lipid transport and sequestration models. However, when combined with orthogonal targeting of SAC1 to the mitochondrial outer membrane, ORP5 facilitates depletion of PM PI4P when targeted to PM-mitochondria contact sites. We conclude that PI4P depletion from the PM by ORP5 requires transport of PI4P to the tethered organelle membrane, which must be closely coupled to PI4P hydrolysis by SAC1. The data are most compatible with a lipid transfer reaction by ORP family members.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 05, 2022.
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Depletion of Plasma Membrane PI4P by ORP5 Requires Hydrolysis by SAC1 in Acceptor Membranes
Colleen P. Doyle, Liz Timple, Gerald R. V. Hammond
bioRxiv 2022.08.04.502856; doi: https://doi.org/10.1101/2022.08.04.502856
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Depletion of Plasma Membrane PI4P by ORP5 Requires Hydrolysis by SAC1 in Acceptor Membranes
Colleen P. Doyle, Liz Timple, Gerald R. V. Hammond
bioRxiv 2022.08.04.502856; doi: https://doi.org/10.1101/2022.08.04.502856

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