The delivery of proteins from the plasma membrane to the lysosome for degradation is essential for normal cellular function. There is now a good understanding of the protein complexes involved in sorting proteins at the plasma membrane and into the intralumenal vesicles of the multi-vesicular body. A combination of cell free content mixing assays and live-cell imaging has dissected out the final step in delivery of macromolecules to the lysosome from the multi-vesicular body and provided insights into the molecular mechanisms by which late endosomes and lysosomes exchange lumenal contents. The endocytic pathway has provided a platform with which to understand the autophagic and phagocytic pathways, but the fine details of how traffic through these pathways is regulated remain to be determined.
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