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Review
. 2008 Mar;129(3):267-76.
doi: 10.1007/s00418-007-0376-5. Epub 2008 Jan 12.

Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity

Kirsten Sandvig  1 , Maria Lyngaas Torgersen, Hilde Andersen Raa, Bo van Deurs
Affiliations
Review

Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity

Kirsten Sandvig et al. Histochem Cell Biol. 2008 Mar.

Abstract

Today it is generally accepted that there are several endocytic mechanisms, both the clathrin-dependent one and mechanisms which operate without clathrin and with different requirements when it comes to dynamin, small GTP-binding proteins of the Rho family and specific lipids. It should be noted that clathrin-independent endocytosis can occur even when the cholesterol level in the membrane has been reduced to so low levels that caveolae are gone and clathrin-coated membrane areas are flat. Although new investigators in the field take it for granted that there is a multitude of entry mechanisms, it has taken a long time for this to become accepted. However, more work needs to be done, because one can still ask the question: How many endocytic mechanisms does a cell have, what are their function, and how are they regulated? This article describes some of the history of endocytosis research and attempts to give an overview of the complexity of the mechanisms and their regulation.

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Figures

Fig. 1
Fig. 1
An overview of a factors involved in different types of endocytosis, and b schematic drawing of polarized MDCK cells where some proteins/enzymes involved in regulation of apical clathrin-independent endocytosis have been listed. It should be noted that apical clathrin-independent endocytosis may consist of more than one mechanism and that polarized MDCK cells have caveolae only at the basolateral surface. For references, see the text
Fig. 2
Fig. 2
Shiga toxin endocytosis is strongly increased upon methyl-β-cyclodextrin-treatment of BHK cells induced for expression of antisense to clathrin heavy chain. BHK cells with inducible expression of antisense to clathrin heavy chain was preincubated with methyl-β-cyclodextrin (10 mM) for 30 min. Then biotin- and TAG-labeled Shiga toxin (25 ng/ml) was added and the cells were incubated for 20 min. Surface-bound and endocytosed Shiga toxin was quantified as previously described for Cholera toxin (Torgersen et al. 2001). The data are presented as internalized toxin as percent of total cell-associated toxin (mean ± SD, n = 4). Endocytosis of transferrin was performed in parallel to verify the inhibition of clathrin-dependent endocytosis upon induction of antisense to clathrin heavy chain. Upon induction, transferrin uptake was reduced by 95%
Fig. 3
Fig. 3
Appearance of caveolae in myoepithelial cells. In (a) is seen a single caveola (Cav) and for comparison a clathrin-coated pit (Cp). b shows a group of caveolae at the plasma membrane; as the section is largely perpendicular to the membrane, most of the caveolae are clearly seen to be surface-connected. In (c) is shown an example of a section which is not perpendicular to the plasma membrane, and here many of the caveolae appears as free (not surface-connected) vesicles. If such “free” vesicles should be unequivocally established as caveolae, they can be immunogold-labeled using an antibody against caveolin, as shown on the ultracryosection in (d) (Cav). An unlabeled, Cp is also seen. Bars 500 nm
Fig. 4
Fig. 4
Caveolae are surface-connected structures. a–d show filter-grown MDCK cells postfixed with the electron-dense cell surface marker Ruthenium Red from the basolateral side. In (a) is seen a number of caveolae connected to the basolateral membrane (arrowheads). Also note that three caveolae (arrows) are connected to the plasma membrane (open arrow) via a larger membrane invagination (asterisk). b–d show clusters of caveolae (arrows) associated with elongated “vacuolar” structures (asterisks) apparently freely localized in the cytoplasm. However, the labelling with Ruthenium Red clearly demonstrates that these structure are indeed connected to the basolateral membrane, as revealed in (a). En, early and later endosomes; Nu, nucleus. Bar 500 nm
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