{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nOxysterol‐binding protein (OSBP) is a multifunctional lipid transfer protein localized at endoplasmic reticulum–Golgi contact sites. Its characteristic architecture—with a plekstrin homology (PH) domain mediating Golgi binding, a FFAT motif targeting the ER via VAP‐A, and a lipid transfer (ORD) domain—enables OSBP to couple membrane tethering with a lipid exchange cycle that drives the transfer of sterols in one direction and phosphatidylinositol 4‐phosphate (PI4P) in the reverse, with PI4P hydrolysis by Sac1 contributing the energy and negative feedback to this cycle."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in interorganelle lipid exchange, OSBP functions as a cholesterol‐binding scaffolding protein that coordinates the assembly of oligomeric phosphatase complexes, including protein phosphatase PP2A and tyrosine phosphatases, to regulate key signaling pathways such as the extracellular signal–regulated kinase (ERK) cascade. Through this assembly, OSBP modulates dephosphorylation events and links cholesterol levels directly to signal transduction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOSBP also integrates sterol regulatory signals with sphingolipid metabolism by regulating ceramide transfer protein (CERT) function at the Golgi apparatus. Its interactions with CERT and VAP facilitate CERT’s translocation, thereby coordinating ceramide transport for sphingomyelin synthesis in response to cholesterol and oxysterol cues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, OSBP plays a critical role in maintaining proper cholesterol distribution and membrane lipid order. It regulates the turnover and spatial distribution of PI4P, consuming a significant portion of the cellular pool and thus influencing the lipid composition along the secretory pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOSBP is exploited by viruses to facilitate their replication and maturation. In hepatitis C virus (HCV)–infected cells, OSBP binds viral proteins (such as NS5A) and forms complexes that modulate phosphatase activity and control ERK signaling—processes pivotal for efficient viral particle release. Similarly, during poliovirus infection, viral proteins modulate OSBP and its related pathways to promote the formation of cholesterol- and PI4P-enriched replication organelles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPhosphorylation plays a central role in regulating OSBP function. Protein kinase D phosphorylates OSBP (notably at Ser240), an event that attenuates its Golgi localization and modulates its capacity to recruit CERT. In parallel, phosphorylation at serine-rich motifs also modulates OSBP’s affinity for cholesterol and its interaction with VAP-A, thus fine-tuning its lipid transfer activity in response to cellular signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural studies have shown that OSBP directly interacts with VAP-A via its FFAT motif, a key interaction essential for its proper targeting to ER–Golgi contact sites. Additionally, recent investigations using schweinfurthin derivatives have demonstrated that small molecules can occupy the lipid-binding cavity of OSBP with nanomolar affinity, thereby inhibiting its lipid exchange cycle and altering downstream lipid signaling processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these diverse functions illustrate that OSBP serves as a central node in lipid homeostasis and signal transduction—exchanging cholesterol and PI4P between membranes, regulating sphingomyelin synthesis, maintaining membrane organization, and even influencing viral replication—roles that are underscored by extensive studies on the OSBP/ORP family."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bruno Mesmin, Joëlle Bigay, Joachim Moser von Filseck, et al. 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