Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER

Muthukumar Kannan,Sujoy Lahiri,Li-Ka Liu,Vineet Choudhary,William A Prinz

doi:10.1194/jlr.m072959

Abstract

Close contacts between organelles, often called membrane contact sites (MCSs), are regions where lipids are exchanged between organelles. Here, we identify a novel mechanism by which cells promote phospholipid exchange at MCSs. Previous studies have shown that phosphatidylserine (PS) synthase activity is highly enriched in portions of the endoplasmic reticulum (ER) in contact with mitochondria. The objective of this study was to determine whether this enrichment promotes PS transport out of the ER. We found that PS transport to mitochondria was more efficient when PS synthase was fused to a protein in the ER at ER-mitochondria contacts than when it was fused to a protein in all portions of the ER. Inefficient PS transport to mitochondria was corrected by increasing tethering between these organelles. PS transport to endosomes was similarly enhanced by PS production in regions of the ER in contact with endosomes. Together, these findings indicate that PS production at MCSs promotes PS transport out of the ER and suggest that phospholipid production at MCSs may be a general mechanism of channeling lipids to specific cellular compartments.

Highlights

Close contacts between organelles, often called membrane contact sites (MCSs), are regions where lipids are exchanged between organelles
We reasoned that if PS production at contacts promotes PS transport to mitochondria, targeting PS synthase to contact sites would result in greater PS transport to mitochondria than when PS synthase is localized all over the endoplasmic reticulum (ER)
We show that enrichment of PS synthase in regions of the ER that are in contact with mitochondria promotes the transfer of newly synthesized PS from the ER to mitochondria

Summary

Introduction

Often called membrane contact sites (MCSs), are regions where lipids are exchanged between organelles. Membrane contact sites (MCSs) are regions where two organelles are closely apposed, often within 30 nm of one another One function of these sites is to facilitate nonvesicular lipid exchange between organelles [1,2,3]. The mechanism of nonvesicular lipid exchange between organelles at MCSs is not well understood, but in most cases probably requires lipid transport proteins (LTPs) [7, 8]. These proteins have domains that can bind lipid monomers in a hydrophobic pocket or cleft, which allows them to shuttle lipids between membranes [7]. Some LTPs are enriched at MCSs, where they would need to diffuse only a short distance between organelles to facilitate lipid exchange

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