Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1

• DOI: 10.1091/mbc.e12-10-0760
• Publication Date: 2013-09-12T02:09:48Z
• Authors: Nicholas L. Cianc...; Diane J. Greene; Richard E. Morton; Cathleen R. Carlin
• Keywords: 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 cholesterol storage phenotype NPC1-mutant fibroblasts. show here reconstitutes deficient endosome-to-endoplasmic reticulum (ER) transport, allowing excess LDL-cholesterol to be esterified acyl-CoA:cholesterol acyltransferase and stored lipid droplets (LDs) NPC1-deficient cells. Furthermore, pathway regulated oxysterol-binding ORP1L. Studies have classified ORP1L as a sterol sensor involved LE positioning downstream GTP-Rab7. Our data, however, suggest may play role transport specific ER pool designated for LD formation. In contrast NPC1, dispensable, RIDα/ORP1L-dependent route requires functional NPC2. Although NPC1/NPC2 constitutes major pathway, therapies amplify minor routes could significantly improve clinical management patients with loss-of-function mutations. The molecular identity putative alternative pathways, poorly characterized. propose model system understanding physiological use activate feedback responses