Triacylglycerols sequester monotopic membrane proteins to lipid droplets

Lucie Caillon,Nicolas Rodriguez,Mohyeddine Omrane,Vincent Nieto,Pauline Gehan,Abdou Rachid Thiam,Luca Monticelli

doi:10.1038/s41467-020-17585-8

Abstract

Triacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs). LDs are covered by a single phospholipid monolayer contiguous with the ER bilayer. This connection is used by several monotopic integral membrane proteins, with hydrophobic membrane association domains (HDs), to diffuse between the organelles. However, how proteins partition between ER and LDs is not understood. Here, we employed synthetic model systems and found that HD-containing proteins strongly prefer monolayers and returning to the bilayer is unfavorable. This preference for monolayers is due to a higher affinity of HDs for TG over membrane phospholipids. Protein distribution is regulated by PC/PE ratio via alterations in monolayer packing and HD-TG interaction. Thus, HD-containing proteins appear to non-specifically accumulate to the LD surface. In cells, protein editing mechanisms at the ER membrane would be necessary to prevent unspecific relocation of HD-containing proteins to LDs.

Highlights

Triacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs)
The LD-water interface is distinguishable from a bilayer-water interface by several features: it can sustain a loose lipid packing[9,15,16]; the thickness of the underlying hydrophobic region, up to hundreds nm, is much larger than the hydrophobic thickness of a bilayer (~3 nm)[17,18]; the hydrophobic core consists of neutral lipids, instead of phospholipid acyl chains
We found that protein distribution is altered by the ratio between PC and PE phospholipids by regulating the extent of hydrophobic membrane association domains (HDs)-TG contact at the LD surface

Summary

Introduction

Triacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs). LDs are covered by a single phospholipid monolayer contiguous with the ER bilayer This connection is used by several monotopic integral membrane proteins, with hydrophobic membrane association domains (HDs), to diffuse between the organelles. The LD-water interface is distinguishable from a bilayer-water interface by several features: it can sustain a loose lipid packing[9,15,16]; the thickness of the underlying hydrophobic region, up to hundreds nm, is much larger than the hydrophobic thickness of a bilayer (~3 nm)[17,18]; the hydrophobic core consists of neutral lipids, instead of phospholipid acyl chains Considering these discrepancies in physical chemistry, it may not be surprising that proteins show preference for one interface over the other. Neither the energetics involved in their binding to LDs nor the parameters controlling their ER-toLD partitioning are known

Methods

Results

Conclusion