Document Detail


The cytosolic adaptor AP-1A is essential for the trafficking and function of Niemann-Pick type C proteins.
MedLine Citation:
PMID:  23350547     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by over-accumulation of low-density lipoprotein-derived cholesterol and glycosphingolipids in late endosomes/lysosomes (LE/L) throughout the body. Human mutations in either NPC1 or NPC2 genes have been directly associated with impaired cholesterol efflux from LE/L. Independent from its role in cholesterol homeostasis and its NPC2 partner, NPC1 was unexpectedly identified as a critical player controlling intracellular entry of filoviruses such as Ebola. In this study, a yeast three-hybrid system revealed that the NPC1 cytoplasmic tail directly interacts with the clathrin adaptor protein AP-1 via its acidic/di-leucine motif. Consequently, a nonfunctional AP-1A cytosolic complex resulted in a typical NPC-like phenotype mainly due to a direct impairment of NPC1 trafficking to LE/L and a partial secretion of NPC2. Furthermore, the mislocalization of NPC1 was not due to cholesterol accumulation in LE/L, as it was not rescued upon treatment with Mβ-cyclodextrin, which almost completely eliminated intracellular free cholesterol. Our cumulative data demonstrate that the cytosolic clathrin adaptor AP-1A is essential for the lysosomal targeting and function of NPC1 and NPC2.
Authors:
Steve Poirier; Gaétan Mayer; Stephanie R Murphy; William S Garver; Ta Yuan Chang; Peter Schu; Nabil G Seidah
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-20
Journal Detail:
Title:  Traffic (Copenhagen, Denmark)     Volume:  14     ISSN:  1600-0854     ISO Abbreviation:  Traffic     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-07     Completed Date:  2013-08-15     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  100939340     Medline TA:  Traffic     Country:  England    
Other Details:
Languages:  eng     Pagination:  458-69     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons A/S.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Protein Complex 1 / metabolism*
Amino Acid Motifs
Animals
Carrier Proteins / metabolism*
Cell Line
Cholesterol / metabolism
Exocytosis
Lysosomes / drug effects,  metabolism
Membrane Glycoproteins / metabolism*
Mice
Protein Interaction Domains and Motifs
Protein Transport
Two-Hybrid System Techniques
Vesicular Transport Proteins / metabolism*
beta-Cyclodextrins / pharmacology
Grant Support
ID/Acronym/Agency:
CTP-82946//Canadian Institutes of Health Research; HL036709/HL/NHLBI NIH HHS; MOP-102741//Canadian Institutes of Health Research; R01 HL036709/HL/NHLBI NIH HHS; T32 GM008704/GM/NIGMS NIH HHS; T32GM008704/GM/NIGMS NIH HHS; UL1 TR000041/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Protein Complex 1; 0/Carrier Proteins; 0/Membrane Glycoproteins; 0/NPC1 protein, human; 0/Npc2 protein, mouse; 0/Vesicular Transport Proteins; 0/beta-Cyclodextrins; 0/methyl-beta-cyclodextrin; 97C5T2UQ7J/Cholesterol
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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