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Vol. 18, Issue 2, 337-347, February 2007

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Internalization of Large Double-Membrane Intercellular Vesicles by a Clathrin-dependent Endocytic Process

Michelle Piehl^*,, Corinna Lehmann^*,,, Anna Gumpert^*, Jean-Pierre Denizot, Dominique Segretain^||, and Matthias M. Falk^*

*Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015; Unité de Neurosciences Intégratives et Computationnelles, Centre National de la Recherche Scientifique UPR 2191, Gif sur Yvette 91198 Cedex, France; and ^||Institut National de la Santé et de la Recherche Médicale U670, Université de Paris 5, Paris, France

Submitted June 5, 2006; Revised October 19, 2006; Accepted November 2, 2006
Monitoring Editor: Asma Nusrat

Beyond its well-documented role in vesicle endocytosis, clathrin has also been implicated in the internalization of large particles such as viruses, pathogenic bacteria, and even latex beads. We have discovered an additional clathrin-dependent endocytic process that results in the internalization of large, double-membrane vesicles at lateral membranes of cells that are coupled by gap junctions (GJs). GJ channels bridge apposing cell membranes to mediate the direct transfer of electrical currents and signaling molecules from cell to cell. Here, we report that entire GJ plaques, clusters of GJ channels, can be internalized to form large, double-membrane vesicles previously termed annular gap junctions (AGJs). These internalized AGJ vesicles subdivide into smaller vesicles that are degraded by endo/lysosomal pathways. Mechanistic analyses revealed that clathrin-dependent endocytosis machinery-components, including clathrin itself, the alternative clathrin-adaptor Dab2, dynamin, myosin-VI, and actin are involved in the internalization, inward movement, and degradation of these large, intercellular double-membrane vesicles. These findings contribute to the understanding of clathrin's numerous emerging functions.

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

These authors contributed equally to this work.

Present address: Olympus Deutschland GmbH, Wendenstrasse 16-18, Hamburg, Germany.

Address correspondence to: Matthias M. Falk (mfalk{at}lehigh.edu)