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Review
. 2020 Jun 18;10(6):928.
doi: 10.3390/biom10060928.

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

Nina Criado Santos  1 , Vladimir Girik  1 , Paula Nunes-Hasler  1
Affiliations
Review

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

Nina Criado Santos et al. Biomolecules. .

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.

Keywords: OSBPL5; OSBPL8; PtdIns; PtdIns(4,5)P2; PtdIns4P; cortical endoplasmic reticulum; oxysterol binding protein like 5 and 8.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of ORP5 and ORP8 isoforms. (A–C) Domain structure of (A) human ORP8L (canonical form) and ORP8S (missing residues 1-43), (B) ORP5A (canonical form) and ORP5B (missing residues 134-201 within the PH domain), and (C) S. cerevisiae Osh6, Osh7 proteins. Acidic amino acids within the N-terminal domain of ORP8L are highlighted in red. Basic amino acids inside the polybasic segments are highlighted in blue. The position of PI(4)P or PS binding motifs within the ORD domains of ORP5, ORP8, Osh6, Osh7 is indicated by green (PI(4)P) or yellow (PS) strips. The positions of the putative amphipathic helices within the ORD domains of ORP5, ORP8 are indicated by pink strips. (d) Residues involved in the recognition of head groups of PI(4)P or PS within the ORD domains of ORP5, ORP8, Osh6, and Osh7. (E) Ribbon representation of the crystal structure of the ORP8 PH domain showing alpha helices (green) and β-sheets (blue), as well as the atypical extended loop 3 (arrow) (PDB id: 1V88). (F) Multiple sequence alignment of the PH domains from human ORP5A, ORP8, OSBP, ORP1 and CERT highlighting the atypical nature of the ORP5 and ORP8 PH domains. Secondary structure elements of ORP5A are indicated above the alignment. Residues comprising the atypical extended loop present in ORP5A and ORP8 but absent in other PH domains are highlighted by the blue box. Basic amino acids found only in the PH domains of ORP5 and ORP8 proteins but absent in other PH domains are indicated by blue arrows. The amino acids mediating PI(4)P binding which are present in CERT but absent in ORP5 and ORP8 are indicated by green triangles [26]. Alignments were made with ESPript version 3.0 [33]. (G) Ribbon representation of the crystal structure of Osh6 ORD bound to PS, the latter shown as a ball-and-stick model (PDB id:4B2Z). The lid covering the barrel is indicated in red. PB: Polybasic segment, PH: Pleckstrin homology domain, ORD: OSBP related domain, TM: transmembrane domain.
Figure 2
Figure 2
ORP5 and 8 function at various membrane contact sites. (A) Endoplasmic reticulum-plasma membrane (ER-PM) membrane contact sites (MCS): ORP5/8 function as phospholipid lipid transfer proteins (LTPs) powered by a counter-flow mechanism, enriching PS at the PM in exchange for PI(4)P which is dephosphorylated in the ER by phosphatase Sac1. Both PI(4)P and PI(4,5)P2 recruit ORP5/8 to the PM through interactions with the PH and PB domains, and PI(4,5)P2 is possibly also transported. ORP5/8-mediated control of PM levels of PS and PIPs may regulate cellular proliferation and migration through the activation of kinases such as KRas and AKT. Sterol sensing may also play a role. ORP8 levels are regulated by miR-143. (B) ER-mitochondria MCS: ORP5/8 interact with the mitochondrial MCS tether PTPIP51 (recruited to MCS by interaction with vesicle-associated membrane protein B (VAPB)) and regulate mitochondrial respiration, morphology, and Ca2+ signaling, potentially through PS enrichment; (C) ER-(endo)-lysosome MCS: ORP5 interacts with cholesterol transporter NPC1 and regulates delivery cholesterol from the limiting membrane to the ER. Whether ORP5 directly transports sterols remains to be confirmed; (D) ORP8 interaction with centrosomal protein SPAG5 inhibits mitosis. ORP8 interaction with the NPC protein NUP62 promotes sterol regulatory binding protein (SREBP) translocation to the nucleus, thereby promoting lipogenesis. ORP8 represses cholesterol transporter ATP binding cassette subfamily A member 1 (ABCA1) expression and cholesterol efflux, potentially through liver X receptor (LXR). ORP8 expression also induces ER stress through a poorly defined mechanism. ORP5 promotes SREBP2 expression, inducing hydroxymethylglutaryl coenzyme A (HMG-CoA)-synthase and histone deacetylase 5 (HDAC5) expression, while reducing phosphatase and tensin homolog (PTEN). This axis potentially contributes to increased proliferation and migration. Whether sterol sensing plays a role in these functions remains to be verified; (E) ER-lipid droplet (LD) MCS: ORP5A and its shorter isoform ORP5B are recruited to LDs via their ORD, exchange PS and PI(4)P on the LD phospholipid monolayer, and control LD size. PBD: polybasic domain, OMM: outer mitochondrial membrane, IMM: inner mitochondrial membrane, ONM: outer nuclear membrane, IMN: inner nuclear membrane, NPC: nuclear pore complex.
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