Autophagy was discovered in the late 1950s when scientists using the first electron microscopes saw membrane-bound structures in cells that contained cytoplasmic organelles, including mitochondria. Pursuant to further morphological characterization it was recognized that these vesicles, now called autophagosomes, are found in all eukaryotic cells and undergo changes in morphology from a double-membraned vesicle with recognizable content, i.e. sequestered organelles, to a uniformly dense core autolysosome. Genetic screens in the yeast Saccharomyces cerevisiae in the 1990s provided a molecule framework for the next era of discovery during which the interest in, and research into, autophagy has rapidly expanded into many areas of human biology and disease. A relatively small cohort of approximately 36 proteins, called Atgs (autophagy-related proteins), orchestrate the formation of the autophagosome, and these are now being studied and functionally characterized. Although the function of these proteins is being elucidated, the underlying molecular mechanisms of how autophagosomes form are still not completely understood. Recent advances have, however, provided a significant advance in both our understanding of the molecular control of the Atg proteins and the source of the membranes. A consensus view is emerging from these advances that the endoplasmic reticulum is the nucleation site for the autophagosome, and that contributions from other compartments (Golgi, endosomes and plasma membrane) are required. In the present chapter, I review the data from the pre-molecular decades, and discuss the most recent publications to give an overview of the current view of where, and how, autophagosomes form in mammalian cells.

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