Mechanisms of autophagy: The machinery of macroautophagy and points of control

Identification of autophagy-related (ATG) genes has been transiting autophagy research from morphological characterization to mechanistic investigation since 1993. ATG genes were first discovered by three genetic screens independently performed in the budding yeast Saccharomyces cerevisiae. Later, conserved orthologs of ATG yeast genes were found in higher organisms including Caenorhabditis elegans, Drosophila, Arabidopsis, and mammals. The core autophagy machinery essential for autophagosome formation and maturation contains more than 20 ATG genes categorized into the following major groups: (1) the Atg1/ULK1 kinase complex; (2) the class III phosphatidylinositol 3-kinase complex; (3) Atg2-Atg18/WIPIs (WD-repeat domain phosphoinositide-interacting proteins); (4) Atg9/ATG9 vesicles; (5) the Atg12-Atg5-Atg16 complex; and (6) Atg8/LC3-PE (phosphatidylethanolamine). Recent advances in structural biology, imaging, and biochemical techniques have led to characterization of the molecular and architectural details of each step in autophagy. This chapter summarizes progress over the last decade on the origin, initiation, expansion, and maturation of autophagosomal membranes.