Document Detail


Regulatory role of β-arrestin-2 in cholesterol processing in cystic fibrosis epithelial cells.
MedLine Citation:
PMID:  22523395     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cystic fibrosis (CF) cells exhibit an increase in the protein expression of β-arrestin-2 (βarr2) coincident with perinuclear accumulation of free cholesterol. Arrestins are proteins that both serve as broad signaling regulators and contribute to G-protein coupled receptor internalization after agonist stimulation. The hypothesis of this study is that βarr2 is an important component in the mechanisms leading to cholesterol accumulation characteristic of CF cells. To test this hypothesis, epithelial cells stably expressing GFP-tagged βarr2 (βarr2-GFP) and respective GFP-expressing control cells (cont-GFP) were analyzed by filipin staining. The βarr2-GFP cells show a late endosomal/lysosomal cholesterol accumulation that is identical to that seen in CF cells. This βarr2-mediated accumulation is sensitive to Rp-cAMPS treatment, and depleting βarr2 expression in CF-model cells by shRNA alleviates cholesterol accumulation compared with controls. Cftr/βarr2 double knockout mice also exhibit wild-type (WT) levels of cholesterol synthesis, and WT profiles of signaling protein expression have previously been shown to be altered in CF due to cholesterol-related pathways. These data indicate a significant regulatory role for βarr2 in the development of CF-like cholesterol accumulation and give further insight into cholesterol processing mechanisms. An impact of βarr2 expression on Niemann-Pick type C-1 (NPC1)-containing organelle movement is proposed as the mechanism of βarr2-mediated alterations on cholesterol processing. It is concluded that βarr2 expression contributes to altered cholesterol trafficking observed in CF cells.
Authors:
Mary E Manson; Deborah A Corey; Ilya Bederman; James D Burgess; Thomas J Kelley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-22
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-11     Completed Date:  2013-02-26     Revised Date:  2014-06-04    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1268-76     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrestins / deficiency,  genetics,  metabolism*
Cells, Cultured
Cholesterol / biosynthesis,  genetics,  metabolism*
Cystic Fibrosis / genetics,  metabolism*
Epithelial Cells / metabolism*,  pathology
Humans
Mice
Mice, Inbred CFTR
Mice, Knockout
Phenotype
Grant Support
ID/Acronym/Agency:
EB-009481/EB/NIBIB NIH HHS; HL-080319/HL/NHLBI NIH HHS; P30 DK027651/DK/NIDDK NIH HHS; P30-DK-27651/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Arrestins; 0/beta-arrestin; 97C5T2UQ7J/Cholesterol
Comments/Corrections

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