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Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814149/ https://www.ncbi.nlm.nih.gov/pubmed/24025716 http://dx.doi.org/10.1091/mbc.E12-10-0760 |
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author | Cianciola, Nicholas L. Greene, Diane J. Morton, Richard E. Carlin, Cathleen R. |
author_facet | Cianciola, Nicholas L. Greene, Diane J. Morton, Richard E. Carlin, Cathleen R. |
author_sort | Cianciola, Nicholas L. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3814149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-38141492014-01-16 Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 Cianciola, Nicholas L. Greene, Diane J. Morton, Richard E. Carlin, Cathleen R. Mol Biol Cell Articles 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. The American Society for Cell Biology 2013-11-01 /pmc/articles/PMC3814149/ /pubmed/24025716 http://dx.doi.org/10.1091/mbc.E12-10-0760 Text en © 2013 Cianciola et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Cianciola, Nicholas L. Greene, Diane J. Morton, Richard E. Carlin, Cathleen R. Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 |
title | Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 |
title_full | Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 |
title_fullStr | Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 |
title_full_unstemmed | Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 |
title_short | Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1 |
title_sort | adenovirus ridα uncovers a novel pathway requiring orp1l for lipid droplet formation independent of npc1 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814149/ https://www.ncbi.nlm.nih.gov/pubmed/24025716 http://dx.doi.org/10.1091/mbc.E12-10-0760 |
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