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First published online June 20, 2008
doi: 10.1242/10.1242/dev.016105

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The cell biology of autophagy in metazoans: a developing story

¹ Department of Biology, Queens College, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
² Department of Genetics, Cell Biology and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.

View larger version (59K): [in this window] [in a new window]   Fig. 1. Schematic representation of autophagy progression in metazoans. (A) In response to starvation or other inductive cues, a membranous sac referred to as the phagophore or isolation membrane is nucleated from a poorly characterized structure known as the pre-autophagosomal structure or phagophore assembly site (PAS). (B) Expansion and curvature of the isolation membrane leads to engulfment of cytosolic material within the double membrane-bound autophagosome. The source of lipid contributing to this membrane growth has not been established. (C) Fusion of the autophagosomal outer membrane with lysosomes results in hydrolytic digestion of the inner membrane and the sequestered material, and export of the breakdown products into the cytoplasm. The prior fusion of autophagosomes with early or late endosomes (forming a structure known as an amphisome, not shown) may be required for autophagosome-lysosome fusion. (D,E) Electron micrographs of corresponding structures, including (D) a nearly completed autophagosome engulfing a mitochondrion, and (E) an auto-lysosome containing several degraded organelles and an intact mitochondrion.

View larger version (11K): [in this window] [in a new window]   Fig. 2. Nutrient-dependent regulation of autophagy. Autophagy proceeds constitutively at a low basal rate in most cells, and can be induced to high levels in response to starvation, loss of growth factor signaling and other stressors. The TOR signaling pathway plays a central role in many of these responses. The kinase activity of TOR is inhibited by Tsc1 and Tsc2, which form a complex, with GAP activity, against the small GTPase Rheb, a direct activator of TOR (Wullschleger et al., 2006). The Tsc1/Tsc2 complex, in turn, is regulated by several upstream protein kinases, including Akt in response to insulin signaling and AMPK in response to AMP/ATP levels. Downstream of TOR, the protein kinases Atg1 and S6K have important roles in autophagy, but the relevant substrates of these kinases have not been determined (Kamada et al., 2000; Scott et al., 2004). In addition, both Atg1 and S6K inhibit TOR signaling through negative feedback loops (Lee et al., 2007; Scott et al., 2007). Signaling levels of reactive oxygen species (ROS) are generated in response to starvation and are required for activation of the autophagy-specific protease Atg4 (Scherz-Shouval et al., 2007). Starvation also inhibits the association of beclin 1/Atg6 with Bcl2, leading to increased autophagic activity of beclin 1 protein (Pattingre et al., 2005). Abbreviations: AMP, adenosine monophosphate; ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase; GAP, GTPase activating protein; S6K, p70 S6 kinase; Tsc, tuberous sclerosis complex.

View larger version (53K): [in this window] [in a new window]   Fig. 3. Evolutionary conservation of the molecular machinery of autophagy. The initial formation of the autophagosome can be divided into distinct steps: (A) induction, (B) vesicle nucleation and (C) vesicle elongation. (A) In yeast, Tor controls the phosphorylation (P) state of Atg13, a protein required for autophagy. Inhibition of Tor causes the dephosphorylation of Atg13 and the subsequent formation of a complex containing Atg1, Atg13, Atg17 and several other proteins, which in turn induces autophagy. Orthologs of Atg13 and Atg1 have been identified in metazoans, but no ortholog to Atg17 has been identified. In metazoans, Tor similarly inhibits autophagy, but whether this is through an interaction between Atg1 and Atg13 or an equivalent protein to Atg17 is not known. (B) The vesicle nucleation step (the formation of the isolation membrane/phagophore) results from the activity of a phosphatidylinositol 3 kinase (PI3K/Vps34) complex, which localizes other pre-autophagosomal proteins to the phagophore. In mammals, Bcl2, Uvrag and Bif1 are part of this complex. Orthologs to all three proteins exist in Drosophila and C. elegans. (C) The vesicle expansion of the phagophore into an autophagosome results from the concerted action of two novel and highly conserved ubiquitin-like conjugation pathways, the Atg12 conjugation system (Atg12p, Atg5p and Atg16p), and the Atg8 lipidation system (Atg8, Atg3 and Atg7). These pathways function in mice; however, it is not known whether the same multimeric structures occur in all metazoans. E1, E1-like ubiquitin activating enzyme; E2, E2-like ubiquitin conjugating enzyme; G, glycine of Atg8; PE, phosphatidylethanolamine that gets covalently linked to Atg8.

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