Document Detail

Cholesterol is required for endocytosis and endosomal escape of adenovirus type 2.
MedLine Citation:
PMID:  14990728     Owner:  NLM     Status:  MEDLINE    
The species C adenovirus type 2 (Ad2) and Ad5 bind the coxsackievirus B Ad receptor and alphav integrin coreceptors and enter epithelial cells by clathrin-mediated endocytosis. This pathway is rapid and efficient. It leads to cell activation and the cholesterol-dependent formation of macropinosomes. Macropinosomes are triggered to release their contents when incoming Ad2 escapes from endosomes. Here, we show that cholesterol extraction of epithelial cells by methyl-beta-cyclodextrin (mbetaCD) treatment reduced Ad5-mediated luciferase expression approximately 4-fold. The addition of cholesterol to normal cells increased gene expression in a dose-dependent manner up to threefold, but it did not restore gene expression in mbetaCD-treated cells. mbetaCD had no effect in the presence of excess cholesterol, indicating that the inhibition of gene expression was due specifically to cholesterol depletion. Cholesterol depletion inhibited rapid Ad2 endocytosis, endosomal escape, and nuclear targeting, consistent with the notion that clathrin-dependent endocytosis of Ad2 is cholesterol dependent. In cholesterol-reduced cells, Ad2 internalized at a low rate, suggestive of an alternative, clathrin-independent, low-capacity entry pathway. While exogenous cholesterol completely restored rapid Ad2 endocytosis, macropinocytosis, and macropinosome disruption, it did not, surprisingly, restore viral escape from endosomes. Our results indicate that macropinosome disruption and endosomal escape of Ad2 are independent events in cells depleted of and then refilled with cholesterol, suggesting that viral escape from endosomes requires lipid-controlled membrane homeostasis, trafficking, or signaling.
Nicola Imelli; Oliver Meier; Karin Boucke; Silvio Hemmi; Urs F Greber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of virology     Volume:  78     ISSN:  0022-538X     ISO Abbreviation:  J. Virol.     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-03-01     Completed Date:  2004-04-08     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3089-98     Citation Subset:  IM    
Zoologisches Institut. Institut für Molekularbiologie, Universität Zürich, CH-8057 Zürich, Switzerland.
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MeSH Terms
Adenoviruses, Human / genetics,  metabolism,  pathogenicity*
Cholesterol / metabolism*
Cytosol / virology
Endosomes / virology*
HeLa Cells
Microscopy, Electron
Reg. No./Substance:

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