title: The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry.
abstract: Vesicle-membrane-protein-associated protein A (VAPA) and oxysterol-binding protein (OSBP) regulate intracellular cholesterol homeostasis, which is required for many virus infections. During entry, viruses or virus-containing vesicles can fuse with endosomal membranes to mediate the cytosolic release of virions, and alterations in endosomal cholesterol can inhibit this invasion step. We show that the antiviral effector protein interferon-inducible transmembrane protein 3 (IFITM3) interacts with VAPA and prevents its association with OSBP, thereby disrupting intracellular cholesterol homeostasis and inhibiting viral entry. By altering VAPA-OSBP function, IFITM3 induces a marked accumulation of cholesterol in multivesicular bodies and late endosomes, which inhibits the fusion of intraluminal virion-containing vesicles with endosomal membranes and thereby blocks virus release into the cytosol. Consequently, ectopic expression or depletion of the VAPA gene profoundly affects IFITM3-mediated inhibition of viral entry. Thus, IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry, further underscoring the importance of cholesterol in virus infection.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Harlyne J. Norris Cancer Research Tower, 1450 Biggy Street, Los Angeles, CA 90033, USA.
authors.forename: Samad
authors.initials: S
authors.lastname: Amini-Bavil-Olyaee
authors.forename: Youn Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Jun Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Mude
authors.initials: M
authors.lastname: Shi
authors.forename: I-Chueh
authors.initials: IC
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism / Q000821:virology; D011992:Endosomes / Q000378:metabolism / Q000821:virology; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D050683:R-SNARE Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D018116:Vesiculovirus / Q000378:metabolism / Q000502:physiology; D014771:Virion / Q000378:metabolism / Q000502:physiology*; D053586:Virus Internalization; D000098825:Oxysterol Binding Proteins
chemical_list: C080082:IFITM3 protein, human; D008565:Membrane Proteins; D050683:R-SNARE Proteins; D016601:RNA-Binding Proteins; D011987:Receptors, Steroid; C114051:VAPA protein, human; D033921:Vesicular Transport Proteins; D000098825:Oxysterol Binding Proteins; D002784:Cholesterol