Oxysterol-binding (OSBP)-related proteins (ORPs) constitute a family of sterol and phosphoinositide binding/transfer proteins in eukaryotes from yeast to man. While their functions have mainly been addressed in cellular lipid metabolism or sterol transport, increasing evidence points to more versatile regulatory roles in a spectrum of cellular regimes. In fact ORPs do not appear to be robust controllers of lipid homeostasis. Several ORPs localize at membrane contacts sites (MCS), where endoplasmic reticulum (ER) is apposed with other organelle limiting membranes. Apparently, ORPs have the capacity to control the formation of MCS or activity of enzymatic machineries at these sites. Thereby, ORPs most likely affect organelle membrane lipid compositions, with impacts on signaling and vesicle transport, but also cellular lipid metabolism. Moreover, an increasing number of protein interaction partners of ORPs have been identified, connecting these proteins with various aspects of cell regulation. Small molecular anti-proliferative compounds, ORPphilins, were recently found to target two members of the ORP family, OSBP and ORP4, revealing an essential function of ORPs in cancer cell proliferation and survival. Further functions assigned for ORPs include regulation of extracellular signal regulated kinase (ERK) activity (OSBP), control of ER-late endosome MCS and late endosome motility (ORP1L), regulation of β1-integrin activity (ORP3), modulation of hepatocyte insulin signaling and macrophage migration (ORP8), as well as post-Golgi vesicle transport, phosphatidylinositol-4-phosphate and target of rapamycin complex 1 signaling and nitrogen sensing (Saccharomyces cerevisiae Osh4p). These and other recent observations shed light on the ORPs as integrators of lipid signals with an unforeseen variety of vital cellular processes.
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