Oxysterol-binding proteins: sterol and phosphoinositide sensors coordinating transport, signaling and metabolism

Abstract

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a family of sterol and phosphoinositide binding proteins conserved in eukaryotes. The mechanisms of ORP function have remained incompletely understood. However, several ORPs are present at membrane contact sites and control the activity of enzymatic effectors or assembly of protein complexes, with impacts on signaling, vesicle transport, and lipid metabolism. An increasing number of protein interaction partners of ORPs have been identified, providing clues of their involvement in multiple aspects of cell regulation. The functions assigned for mammalian ORPs include coordination of sterol and sphingolipid metabolism and mitogenic signaling (OSBP), control of ER-late endosome (LE) contacts and LE motility (ORP1L), neutral lipid metabolism (ORP2), cell adhesion (ORP3), cholesterol eggress from LE (ORP5), macrophage lipid homeostasis, migration and high-density lipoprotein metabolism (ORP8), apolipoprotein B-100 secretion (ORP10), and adipogenesis (ORP11). The anti-proliferative ORPphilin compounds target OSBP and ORP4, revealing a function of ORPs in cell proliferation and survival. The Saccharomyces cerevisiae OSBP homologue (Osh) proteins execute multifaceted functions in sterol and sphingolipid homeostasis, post-Golgi vesicle transport, as well as phosphatidylinositol-4-phosphate and target of rapamycin complex 1 (TORC1) signaling. These observations identify ORPs as coordinators of lipid signals with an unforeseen variety of cellular processes.

Keywords: Cell signaling; ER; ERK; FFAT; KC; LE; Lipid metabolism; MCS; Membrane contact site; OHC; ORD; ORP; OSBP; OSBP-related ligand-binding domain; OSBP-related protein; OSBPL; Oxysterol; PI4P; PIP; PM; VAMP; VAMP-associated protein; VAP; endoplasmic reticulum; extracellular signal-regulated kinase; hydroxycholesterol; ketocholesterol; late endosome; membrane contact site; oxysterol-binding protein; oxysterol-binding protein-like; phosphatidylinositol phosphate; phosphatidylinositol-4-phosphate; plasma membrane; two phenylalanines in an acidic tract; vesicle-associated membrane protein.