Cholesterol-sensitive modulation of transcytosis.
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-beta-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.
Leyt
Julieta
J
Department of Cell and Animal Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
Melamed-Book
Naomi
N
Vaerman
Jean-Pierre
JP
Cohen
Shulamit
S
Weiss
Aryeh M
AM
Aroeti
Benjamin
B
D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity; D002784:Cholesterol / Q000378:metabolism*; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D021962:Membrane Microdomains / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D047392:beta-Cyclodextrins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
D051242:Caveolin 1; C045281:IgA receptor; D007070:Immunoglobulin A; D008024:Ligands; C509763:Rab25 protein, human; D011961:Receptors, Fc; D011990:Receptors, Transferrin; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D020691:rab GTP-Binding Proteins