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Review
. 2014 Jan;24(1):24-41.
doi: 10.1038/cr.2013.168. Epub 2013 Dec 24.

The machinery of macroautophagy

Yuchen Feng  1 , Ding He  1 , Zhiyuan Yao  1 , Daniel J Klionsky  1
Affiliations
Review

The machinery of macroautophagy

Yuchen Feng et al. Cell Res. 2014 Jan.

Abstract

Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.

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Figures

Figure 1
Figure 1
Schematic depiction of the two main types of yeast autophagy. In macroautophagy, random cytoplasm and dysfunctional organelles are sequestered by the expanding phagophore, leading to the formation of the autophagosome. The autophagosome subsequently fuses with the vacuole membrane, releasing the autophagic body into the vacuole lumen. Eventually, the sequestered cargos are degraded or processed by vacuolar hydrolases. In microautophagy, cargos are directly taken up by the invagination of the vacuole membrane, followed by scission, and subsequent lysis, exposing the cargo to vacuolar hydrolases for degradation.
Figure 2
Figure 2
Yeast Atg1 kinase complex. The yeast Atg1 kinase complex includes Atg1, a Ser/Thr protein kinase, Atg13, a regulatory subunit required for Atg1 kinase activity, and the Atg17-Atg31-Atg29 complex, which may function in part as a scaffold. Atg31 bridges Atg17 and Atg29, Atg17 binds Atg13, and Atg29 binds Atg11.
Figure 3
Figure 3
Trafficking of yeast Atg9. In yeast cells, Atg9 is a transmembrane protein that transits between the PAS and peripheral sites (Atg9 reservoirs). Atg9 localization to the PAS from the peripheral sites depends on Atg11, Atg23 and Atg27. Return to the peripheral sites requires Atg1-Atg13, Atg2 and Atg18; PAS recruitment of the latter involves binding to PtdIns3P, the product of the class III PtdIns3K complex.
Figure 4
Figure 4
Yeast PtdIns3K complex I. In yeast, Vps15 (a putative regulatory protein kinase that is required for Vps34 membrane association), Vps30/Atg6, Vps34 (the PtdIns3K), Atg14 and Atg38 form the autophagy-specific class III PtdIns3K complex, which localizes at the PAS. Vps15, Vps34 and Vps30 are present in the second class III PtdIns3K complex that includes Vps38 instead of Atg14.
Figure 5
Figure 5
Yeast Ubl conjugation systems. There are two Ubl protein conjugations systems, involving Atg8 and Atg12, which are used to generate the conjugation products Atg8–PE and Atg12–Atg5, respectively. Atg8 is initially processed by Atg4, a cysteine protease, and during autophagy, Atg8 is released from Atg8–PE by a second Atg4-dependent cleavage. The Atg12–Atg5 conjugate, along with Atg16, facilitates the conjugation of Atg8 to PE. Both of the Ubl protein conjugation systems share a single activating enzyme, Atg7. The conjugating enzymes are Atg3 for Atg8, and Atg10 for Atg12.
Figure 6
Figure 6
Schematic depiction of the mechanism of selective autophagy. Using mitophagy and pexophagy as examples, the model of ligand-receptor-scaffold complex is shown, with Pex3 functioning as a ligand, Atg36 and Atg32 as receptors and Atg11 as the scaffold protein; in the case of mitophagy there does not appear to be a separate ligand on the cargo since Atg32 is an integral membrane protein of the mitochondrial outer membrane.
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