title: Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1.
abstract: Niemann-Pick disease type C (NPC) is caused by mutations in NPC1 or NPC2, which coordinate egress of low-density-lipoprotein (LDL)-cholesterol from late endosomes. We previously reported that the adenovirus-encoded protein RIDα rescues the cholesterol storage phenotype in NPC1-mutant fibroblasts. We show here that RIDα reconstitutes deficient endosome-to-endoplasmic reticulum (ER) transport, allowing excess LDL-cholesterol to be esterified by acyl-CoA:cholesterol acyltransferase and stored in lipid droplets (LDs) in NPC1-deficient cells. Furthermore, the RIDα pathway is regulated by the oxysterol-binding protein ORP1L. Studies have classified ORP1L as a sterol sensor involved in LE positioning downstream of GTP-Rab7. Our data, however, suggest that ORP1L may play a role in transport of LDL-cholesterol to a specific ER pool designated for LD formation. In contrast to NPC1, which is dispensable, the RIDα/ORP1L-dependent route requires functional NPC2. Although NPC1/NPC2 constitutes the major pathway, therapies that amplify minor egress routes for LDL-cholesterol could significantly improve clinical management of patients with loss-of-function NPC1 mutations. The molecular identity of putative alternative pathways, however, is poorly characterized. We propose RIDα as a model system for understanding physiological egress routes that use ORP1L to activate ER feedback responses involved in LD formation.
authors.affiliation: Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195 Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Cianciola
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Greene
authors.forename: Richard E
authors.initials: RE
authors.lastname: Morton
authors.forename: Cathleen R
authors.initials: CR
authors.lastname: Carlin
mesh_terms: D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D004951:Esterification; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins; D000098825:Oxysterol Binding Proteins
chemical_list: D017503:Adenovirus E3 Proteins; D002352:Carrier Proteins; D008078:Cholesterol, LDL; C113428:E3-13.7 protein, human adenovirus; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D011987:Receptors, Steroid; D033921:Vesicular Transport Proteins; D000098825:Oxysterol Binding Proteins
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