Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid

Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from mo...

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Main Authors: Leslie A McCauliff, Annette Langan, Ran Li, Olga Ilnytska, Debosreeta Bose, Miriam Waghalter, Kimberly Lai, Peter C Kahn, Judith Storch
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2019-10-01
Series:eLife
Subjects:
Online Access:https://elifesciences.org/articles/50832
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author Leslie A McCauliff
Annette Langan
Ran Li
Olga Ilnytska
Debosreeta Bose
Miriam Waghalter
Kimberly Lai
Peter C Kahn
Judith Storch
author_facet Leslie A McCauliff
Annette Langan
Ran Li
Olga Ilnytska
Debosreeta Bose
Miriam Waghalter
Kimberly Lai
Peter C Kahn
Judith Storch
author_sort Leslie A McCauliff
collection DOAJ
description Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (PG), is entirely ineffective, indicating an obligate functional interaction between NPC2 and LBPA in cholesterol trafficking. We further demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Together these studies reveal a heretofore unknown step of intracellular cholesterol trafficking which is critically dependent upon the interaction of LBPA with functional NPC2 protein.
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spelling doaj.art-750b28a7bf79492ea5ac11880621e7372022-12-22T02:05:09ZengeLife Sciences Publications LtdeLife2050-084X2019-10-01810.7554/eLife.50832Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acidLeslie A McCauliff0https://orcid.org/0000-0002-5744-2737Annette Langan1Ran Li2Olga Ilnytska3Debosreeta Bose4Miriam Waghalter5Kimberly Lai6Peter C Kahn7Judith Storch8https://orcid.org/0000-0001-5482-1777Department of Nutritional Sciences, Rutgers University, New Brunswick, United States; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United States; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United States; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United States; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United States; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United StatesDepartment of Biochemistry and Microbiology, Rutgers University, New Brunswick, United StatesDepartment of Nutritional Sciences, Rutgers University, New Brunswick, United States; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, United StatesUnesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (PG), is entirely ineffective, indicating an obligate functional interaction between NPC2 and LBPA in cholesterol trafficking. We further demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Together these studies reveal a heretofore unknown step of intracellular cholesterol trafficking which is critically dependent upon the interaction of LBPA with functional NPC2 protein.https://elifesciences.org/articles/50832Niemann Pick Clysosomal storage diseasecholesterolNPC2lipid-protein interactionlysobisphosphatidic acid
spellingShingle Leslie A McCauliff
Annette Langan
Ran Li
Olga Ilnytska
Debosreeta Bose
Miriam Waghalter
Kimberly Lai
Peter C Kahn
Judith Storch
Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid
eLife
Niemann Pick C
lysosomal storage disease
cholesterol
NPC2
lipid-protein interaction
lysobisphosphatidic acid
title Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid
title_full Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid
title_fullStr Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid
title_full_unstemmed Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid
title_short Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid
title_sort intracellular cholesterol trafficking is dependent upon npc2 interaction with lysobisphosphatidic acid
topic Niemann Pick C
lysosomal storage disease
cholesterol
NPC2
lipid-protein interaction
lysobisphosphatidic acid
url https://elifesciences.org/articles/50832
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