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Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes.

ABSTRACT: Cells rely on the correct sorting of endocytic ligands and receptors for proper function. Early endosomes have been considered as the initial sorting station where cargos for degradation separate from those for recycling. Using live-cell imaging to monitor individual endosomes and ligand particles in real time, we have discovered a sorting mechanism that takes place prior to early endosome entry. We show that early endosomes are in fact comprised of two distinct populations: a dynamic population that is highly mobile on microtubules and matures rapidly toward late endosomes and a static population that matures much more slowly. Several cargos destined for degradation are preferentially targeted to the dynamic endosomes, whereas the recycling ligand transferrin is nonselectively delivered to all early endosomes and effectively enriched in the larger, static population. This pre-early endosome sorting process begins at clathrin-coated vesicles, depends on microtubule-dependent motility, and appears to involve endocytic adaptors.

SUBMITTER: Lakadamyali M

PROVIDER: S-EPMC2660893 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes.

Lakadamyali Melike M Rust Michael J MJ Zhuang Xiaowei X

Cell 20060301 5

Cells rely on the correct sorting of endocytic ligands and receptors for proper function. Early endosomes have been considered as the initial sorting station where cargos for degradation separate from those for recycling. Using live-cell imaging to monitor individual endosomes and ligand particles in real time, we have discovered a sorting mechanism that takes place prior to early endosome entry. We show that early endosomes are in fact comprised of two distinct populations: a dynamic population ...[more]

PMID: 16530046

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Project description:Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB) is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME) for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR), and distinct mechanism(s) that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may improve targeted drug delivery.

Dataset Information

Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes.

Publications

Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes.

Similar Datasets

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