SnapShot: Macroautophagy

(Middle) Cellular Events in Macroautophagy Macroautophagy (hereafter referred to as autophagy) is a catabolic process in which portions of the cytoplasm are sequestered within double-or multimembraned vesicles termed autophagosomes and then delivered to lysosomes for bulk degradation. The initial phases of macroautophagy consist of the formation of a phago-phore, which is also called an isolation membrane (vesicle nucleation step), the engulfment of cytoplasmic material—cytosol and/or organelles—by the phagophore, the elongation of the phagophore membrane, and fusion of its edges to form the autophagosome (vesicle elongation and completion steps). In yeast, the pre-au-tophagosomal structure (PAS), consisting of the phagophore or its precursor and autophagy (Atg) proteins, is thought to be the site for assembly of the autophago-some. The outer membrane of the autophagosome fuses with the vacuole in yeast to form the autophagic body or with the lysosome in mammalian cells to form the autolysosome, which is also called the autophagolysosome (docking and fusion steps). Inside the autophagic body/autolysosome, the luminal material including the internal membrane is degraded by vacuolar/lysosome hydrolases (vesicle breakdown and degradation steps). The resulting macromolecules are released through permeases and recycled in the cytosol. Alternatively (not depicted here), the autophagosome may fuse with an endosome to form an amphisome, prior to fusion with the lysosome. Depicted are the molecular pathways of autophagy in yeast (right) and mammals (human or mouse) (left). Although many of the regulators and executors of yeast autophagy have orthologs in mammals (blue shaded ovals), not all yeast autophagy (ATG) genes have a known mammalian equivalent or vice versa. The autophagic machinery in other model eukaryotic organisms (e.g., Dictyostelium discoideum, Arabidopsis thaliana, Drosophila melanogaster, Caenorhabditis elegans) overlaps considerably, but lacks complete convergence, with that of yeast or mammals. In yeast, autophagy is inhibited by the TOR serine/threonine kinase when nutrients are abundant. TOR may inhibit autophagy by indirectly or directly phosphorylating Atg13, which results in its reduced affinity for Atg1 kinase and dissociation from the autophagy-inducing complex. Upon nutrient starvation—the best-characterized physiological inducer of autophagy—TOR is repressed causing the association of dephosphorylated Atg13 with Atg1 and other factors, which stimulates Atg1 catalytic activity and induces autophagy. Similarly, autophagy is stimulated in mammalian cells by nutrient deprivation, which may act through mTOR repression or other as-of-yet undefined mechanisms that activate the class III PI3K complex in an mTOR-independent manner. In mammals, autophagy is also stimulated by deprivation of insulin and other growth factors, which signal …