PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER–plasma membrane contacts

Abstract

Lipid transfer between cell membrane bilayers at contacts between the endoplasmic reticulum (ER) and other membranes help to maintain membrane lipid homeostasis. We found that two similar ER integral membrane proteins, oxysterol-binding protein (OSBP)–related protein 5 (ORP5) and ORP8, tethered the ER to the plasma membrane (PM) via the interaction of their pleckstrin homology domains with phosphatidylinositol 4-phosphate (PI4P) in this membrane. Their OSBP-related domains (ORDs) harbored either PI4P or phosphatidylserine (PS) and exchanged these lipids between bilayers. Gain- and loss-of-function experiments showed that ORP5 and ORP8 could mediate PI4P/PS counter transport between the ER and the PM, thus delivering PI4P to the ER-localized PI4P phosphatase Sac1 for degradation and PS from the ER to the PM. This exchange helps to control plasma membrane PI4P levels and selectively enrich PS in the PM.

Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease

“…We then performed acute insulin challenges as well as shorter 2-hour refeeding experiments to analyze whether early signaling events could explain the increased SREBP-1 activity. Insulin did not induce an additional increase in AKT phosphorylation or a consistent induction of early response genes, such as activating transcription factor 3 (Atf3) or early growth response 1 (Egr1) (Supple- recently implicated in the shuttling of lipids between the plasma and endoplasmic reticulum membrane (12)(13)(14). The expression of Osbpl3, and to a lesser extent Osbpl1a, was robustly induced in LRH-1 K289R livers, while that of most other OSBP family members did not differ between the 2 genotypes ( Figure 2A).…”

“…Triglycerides, free fatty acids, and cholesterol contents in plasma and/or hepatic lipid fractions were quantified using enzymatic assays (Roche). To asses fatty acid synthesis rates in vivo, mice received sodium [1][2][3][4][5][6][7][8][9][10][11][12][13] C] acetate via their drinking water (2%) 24 hours prior to sacrifice. Fatty acids derived from hepatic lipid extracts were liberated, derivatized, and subjected to gas chromatography-mass spectrometry (GC-MS) analysis in order to calculate the fractional synthesis rates from the incorporation of 13 C-acetate as described previously (51).…”

TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

“…For example, the formation and maintenance of ER-plasma membrane junctions depends on tricalbins and other proteins in yeast cells (8)(9)(10) and in mammalian cells on the extended synaptotagmins (E-Syts), a family of three tricalbin homologs, and other unidentified proteins (11,12). The insights from yeast extend to the mechanisms of cellular lipid metabolism and lipid transfer between the apposed bilayers that have been conserved from yeast cells to human cells (13)(14)(15)(16)(17)(18)(19). On the other hand, parallels with yeast are less informative about processes specific to mammalian cells, including the storedependent calcium entry controlled by STIM-ORAI signaling.…”

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

“…Cholesterol transfer is also inhibited by acute gene silencing of ORP5, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs) tethered on ER membranes, and the endocytic regulatory protein HRS (hepatocyte growth factor-regulated tyrosine kinase substrate), which initiates protein sorting in early endosomes (25)(26)(27)(28). Although ORP5 forms a molecular complex with NPC1, its precise role in cholesterol trafficking remains uncertain since ORP5 regulates lipid exchange between the plasma membrane and the ER (25,29). HRS regulates cholesterol transport upstream of NPC1 and NPC2, perhaps by organizing membrane subdomains required for cholesterol transport or initiating formation of stable membrane contacts where NPC1-ORP5 protein complexes eventually assemble in late endosomes (26,30).…”