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Review
. 2008 Aug;135(14):2347-60.
doi: 10.1242/dev.016105.

The cell biology of autophagy in metazoans: a developing story

Alicia Meléndez  1 , Thomas P Neufeld
Affiliations
Review

The cell biology of autophagy in metazoans: a developing story

Alicia Meléndez et al. Development. 2008 Aug.

Abstract

The cell biological phenomenon of autophagy (or ;self-eating') has attracted increasing attention in recent years. In this review, we first address the cell biological functions of autophagy, and then discuss recent insights into the role of autophagy in animal development, particularly in C. elegans, Drosophila and mouse. Work in these and other model systems has also provided evidence for the involvement of autophagy in disease processes, such as neurodegeneration, tumorigenesis, pathogenic infection and aging. Insights gained from investigating the functions of autophagy in normal development should increase our understanding of its roles in human disease and its potential as a target for therapeutic intervention.

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Figures

Figure 1
Figure 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. 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.
Figure 2
Figure 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 Bcl-2, leading to increased autophagic activity of Beclin 1 (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.
Figure 3
Figure 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, Bcl-2, UVRAG, and Bif 1 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.
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References

    1. Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65. - PubMed
    1. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 2007;117:326–36. - PMC - PubMed
    1. Andrade RM, Wessendarp M, Gubbels MJ, Striepen B, Subauste CS. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Invest. 2006;116:2366–77. - PMC - PubMed
    1. Baehrecke EH. Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol. 2005;6:505–10. - PubMed
    1. Barbieri M, Bonafe M, Franceschi C, Paolisso G. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab. 2003;285:E1064–71. - PubMed

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