Document Detail

Mechanism of polarized lysosome exocytosis in epithelial cells.
MedLine Citation:
PMID:  23038769     Owner:  NLM     Status:  MEDLINE    
Fusion of lysosomes with the plasma membrane is a calcium-dependent process that is crucial for membrane repair, limiting pathogen entry and clearing cellular debris. In non-polarized cells, lysosome exocytosis facilitates rapid resealing of torn membranes. Here, we investigate the mechanism of lysosome exocytosis in polarized epithelia, the main barrier between the organism and the external environment and the first line of defense against pathogens. We find that in polarized Madin-Darby canine kidney (MDCK) cells, calcium ionophores or pore-forming toxins cause lysosomes to fuse predominantly with the basolateral membrane. This polarized exocytosis is regulated by the actin cytoskeleton, membrane cholesterol and the clathrin adaptor AP-1. Depolymerization of actin, but not microtubules, causes apical lysosome fusion, supporting the hypothesis that cortical actin is a barrier to exocytosis. Overloading lysosomes with cholesterol inhibits exocytosis, suggesting that excess cholesterol paralyzes lysosomal traffic. The clathrin adaptor AP-1 is responsible for accurately targeting syntaxin 4 to the basolateral domain. In cells lacking either the ubiquitous AP-1A or the epithelial-specific AP-1B, syntaxin 4 is non-polar. This causes lysosomes to fuse with both the apical and basolateral membranes. Consistent with these findings, RNAi-mediated depletion of syntaxin 4 inhibits basolateral exocytosis in wild-type MDCK, and both apical and basolateral exocytosis in cells lacking AP-1A or AP-1B. Our results provide fundamental insight into the molecular machinery involved in membrane repair in polarized epithelia and suggest that AP-1 is a crucial regulator of this process.
Jin Xu; Kimberly A Toops; Fernando Diaz; Jose Maria Carvajal-Gonzalez; Diego Gravotta; Francesca Mazzoni; Ryan Schreiner; Enrique Rodriguez-Boulan; Aparna Lakkaraju
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-04
Journal Detail:
Title:  Journal of cell science     Volume:  125     ISSN:  1477-9137     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2013-02-28     Completed Date:  2014-01-29     Revised Date:  2014-02-28    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  5937-43     Citation Subset:  IM    
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MeSH Terms
Actins / metabolism
Adaptor Protein Complex 1 / metabolism
Calcium / metabolism
Cholesterol / metabolism
Epithelial Cells / metabolism*
Exocytosis / physiology
Lysosomes / metabolism*
Madin Darby Canine Kidney Cells
Grant Support
Reg. No./Substance:
0/Actins; 0/Adaptor Protein Complex 1; 97C5T2UQ7J/Cholesterol; SY7Q814VUP/Calcium
Erratum In:
J Cell Sci. 2013 Nov 1;126(Pt 21):5086

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