ORP5 and ORP8: Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?

Nina Criado Santos,Paula Nunes-Hasler,Vladimir Girik

doi:10.3390/biom10060928

Abstract

Oxysterol binding related proteins 5 and 8 (ORP5 and ORP8) are two close homologs of the larger oxysterol binding protein (OSBP) family of sterol sensors and lipid transfer proteins (LTP). Early studies indicated these transmembrane proteins, anchored to the endoplasmic reticulum (ER), bound and sensed cholesterol and oxysterols. They were identified as important for diverse cellular functions including sterol homeostasis, vesicular trafficking, proliferation and migration. In addition, they were implicated in lipid-related diseases such as atherosclerosis and diabetes, but also cancer, although their mechanisms of action remained poorly understood. Then, alongside the increasing recognition that membrane contact sites (MCS) serve as hubs for non-vesicular lipid transfer, added to their structural similarity to other LTPs, came discoveries showing that ORP5 and 8 were in fact phospholipid transfer proteins that rather sense and exchange phosphatidylserine (PS) for phosphoinositides, including phosphatidylinositol-4-phosphate (PI(4)P) and potentially phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2). Evidence now points to their action at MCS between the ER and various organelles including the plasma membrane, lysosomes, mitochondria, and lipid droplets. Dissecting exactly how this unexpected phospholipid transfer function connects with sterol regulation in health or disease remains a challenge for future studies.

Highlights

Lipid bilayers are integral structural components of cells, allowing the compartmentalization of biomolecules and reactions that make life possible
Early studies examining the role of ORP5 and 8 and their yeast counterparts Osh6 and Osh7 showed clear indications that these members of the oxysterol binding protein (OSBP) family participate in the regulation of cholesterol localization and metabolism both at the cellular and organismal levels
It would be paramount to first more solidly establish whether ORP5 or 8 can or cannot directly transport sterols across membrane contact sites (MCS), and if they can where and under what circumstances

Summary

Introduction

Lipid bilayers are integral structural components of cells, allowing the compartmentalization of biomolecules and reactions that make life possible. Addition of rapamycin led to an acute and rapid dissociation of the PI(4)P-binding probe from the PM as well as the recruitment of a PS-binding probe These results suggest that ORP5 and ORP8 mediate PI(4)P/PS counter-transport between the ER and the PM, helping to control PI(4)P levels while selectively enriching PS at the PM, with dephosphorylation of PI(4)P in the ER by Sac powering the lipid exchange in a manner similar to OSBP at ER-Golgi MCS [20]. Knockdown of ORP5 let to an increase in LD size, whereas overexpression of wild-type ORP5A, but not of PSor PI(4)P-binding mutants produced the reverse effect These results suggest that the phospholipid transfer activity is required for the targeting to and functional effect on LD size. Whether sterol sensing or transfer contributes to the function of ORP5 at LDs should be addressed in future studies

Conclusions and Future Directions

E Cholesterol