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Vol. 18, Issue 6, 2057-2071, June 2007

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Cholesterol-sensitive Modulation of Transcytosis

Julieta Leyt^*, Naomi Melamed-Book, Jean-Pierre Vaerman, Shulamit Cohen^*, Aryeh M. Weiss^,, and Benjamin Aroeti^*

*Department of Cell and Animal Biology and Confocal Unit, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel; Experimental Medicine, Universite Catholique de Louvain and Christian de Duve Institute of Cell Pathology, B-1200 Brussels, Belgium; and School of Engineering, Bar Ilan University, Ramat Gan 52900, Israel

Submitted August 22, 2006; Revised March 15, 2007; Accepted March 21, 2007
Monitoring Editor: Keith Mostov

Cholesterol-rich membrane domains (e.g., lipid rafts) are thought to act as molecular sorting machines, capable of coordinating the organization of signal transduction pathways within limited regions of the plasma membrane and organelles. The significance of these domains in polarized postendocytic sorting is currently not understood. We show that dimeric IgA stimulates the incorporation of its receptor into cholesterol-sensitive detergent-resistant membranes confined to the basolateral surface/basolateral endosomes. A fraction of human transferrin receptor was also found in basolateral detergent-resistant membranes. Disrupting these membrane domains by cholesterol depletion (using methyl--cyclodextrin) before ligand-receptor internalization caused depolarization of traffic from endosomes, suggesting that cholesterol in basolateral lipid rafts plays a role in polarized sorting after endocytosis. In contrast, cholesterol depletion performed after ligand internalization stimulated cargo transcytosis. It also stimulated caveolin-1 phosphorylation on tyrosine 14 and the appearance of the activated protein in dimeric IgA-containing apical organelles. We propose that cholesterol depletion stimulates the coupling of transcytotic and caveolin-1 signaling pathways, consequently prompting the membranes to shuttle from endosomes to the plasma membrane. This process may represent a unique compensatory mechanism required to maintain cholesterol balance on the cell surface of polarized epithelia.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Benjamin Aroeti (aroeti{at}cc.huji.ac.il).

Abbreviations used: DIgA, dimeric IgA; pIgR, polymeric immunoglobulin receptor; MDCK, Madin Darby canine kidney; ZO1, zonula occludens-1; DRMs, detergent-resistant membranes; mCD, methyl- -cyclodextrin; mCD/chol, mCD saturated with cholesterol; Cav1, caveolin-1; SC, secretory component; AREs, apical recycling endosomes; hTfn, human transferrin; hTfnR, human transferrin receptor; pY14-Cav1, Cav1 phosphorylated on Tyr14; IP, immunoprecipitation.