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Review
. 2010 Sep;21(7):664-70.
doi: 10.1016/j.semcdb.2010.03.009. Epub 2010 Mar 30.

Regulation of macroautophagy in Saccharomyces cerevisiae

Yuko Inoue  1 , Daniel J Klionsky
Affiliations
Review

Regulation of macroautophagy in Saccharomyces cerevisiae

Yuko Inoue et al. Semin Cell Dev Biol. 2010 Sep.

Abstract

Macroautophagy (hereafter autophagy) is a cellular degradation process, which in yeast is induced in response to nutrient deprivation. In this process, a double-membrane vesicle, an autophagosome, surrounds part of the cytoplasm and fuses with the vacuole to allow the breakdown and subsequent recycling of the cargo. In yeast, many autophagy-related (ATG) genes have been identified that are required for selective and/or nonselective autophagy. In all autophagy-related pathways, core Atg proteins are required for the formation of the autophagosome, which is one of the most unique aspects of autophagy and is unlike other vesicle transport events. In contrast to nonselective autophagy, the selective processes are induced in response to various specific physiological conditions such as alterations in the carbon source. In this review, we provide an overview of the common aspects concerning the mechanism of autophagy-related pathways, and highlight recent advances in our understanding of the machinery that controls autophagy induction in response to nutrient starvation conditions.

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Figures

Figure 1
Figure 1. Autophagy in the yeast Saccharomyces cerevisiae
In this process, a double-membrane phagophore is generated in the cytosol, which involves nucleation at the phagophore assembly site (PAS). The phagophore enwraps cellular components and expands to form a double-membrane vesicle termed an autophagosome. The outer membrane of the autophagosome ultimately fuses with vacuole membrane. As a result, the inner membrane, which encloses the cargo, is released into the vacuole lumen. The intravacuolar single-membrane vesicle, termed an autophagic body, is lysed, exposing the cargo to a range of hydrolytic enzymes. The resulting degradation products are released back into the cytosol for reuse.
Figure 2
Figure 2. Identification of 33 Atg proteins
Currently, there are 33 autophagy-related (Atg) proteins in fungi that have been identified by various screens. Seventeen core Atg proteins are required for all autophagy-related pathways, and most function at the stage of autophagosome formation. Another sixteen proteins have more specific roles. These latter components are typically involved in the induction of particular autophagy-related pathways in response to different physiological conditions and/or the recognition of selective cargos.
Figure 3
Figure 3. Molecular mechanism of autophagosome formation
Most of the core Atg proteins function at the stage of autophagosome formation. A. Recycling of Atg9. Atg9 is an integral membrane protein, and it localizes to the PAS as well as multiple peripheral sites that are putative membrane sources for the forming autophagosome. Atg9 shuttles between these peripheral sites and the PAS. Atg11, Atg23 and Atg27 are involved in anterograde movement of Atg9 to the PAS, whereas Atg1-Atg13 and Atg2-Atg18 are required for retrograde movement back to the peripheral sites. B. Two ubiquitin-like conjugation systems. Both Atg8 and Atg12 are ubiquitin-like proteins that are involved in two separate conjugation systems. Atg12 is activated by Atg7, and transferred to Atg10, which conjugates it to an internal lysine of Atg5. The Atg12–Atg5 conjugate binds Atg16, which self-oligomerizes to generate a dimer. The Atg12–Atg5-Atg16 complex localizes to the PAS and to the surface of the phagophore. After, or upon, the completion of the autophagosome, these proteins are released from the surface of the vesicle and are reused. Atg8 is initially processed by Atg4 to expose a C-terminal glycine residue. The processed Atg8 is then activated by Atg7, and conjugated by Atg3 to form an amide bond with phosphatidylethanolamine (PE). Atg4 also plays a role as a deconjugation enzyme; a second cleavage event removes Atg8 from PE. Thus, the Atg8 is released from the surface of the autophagosome, whereas the Atg8–PE that remains bound to the inner surface of the completed autophagosome is delivered to the vacuole and degraded. C. Degradation of the autophagic body in the vacuole. Atg15 is a putative lipase, and is needed for lysis of the single-membrane vesicle, the autophagic body, in the vacuole lumen. After breakdown of the cargo by vacuolar hydrolases, the products are released back into the cytosol through permeases such as Atg22.
Figure 4
Figure 4. Induction of autophagy in response to starvation conditions
In nutrient rich conditions, TORC1 is active, and it phosphorylates Atg13. Phosphorylated Atg13 is not able to bind efficiently to Atg1. In starvation conditions, TORC1 is inactivated, and Atg13 is partially dephosphorylated, increasing its affinity for Atg1. Atg1-Atg13 interacts with Atg17-Atg29-Atg31 to form the Atg1 kinase complex; Atg1 kinase activity is enhanced in nutrient starvation conditions by the formation of this complex. PKA is also a negative regulator of autophagy, and its downstream targets include Rim15 kinase and the Msn2/Msn4 transcription factors. PKA also phosphorylates Atg1 and Atg13. It is likely that phosphorylation of a single substrate such as Atg1 is not the sole mechanism of PKA inhibition. In addition to PKA, Sch9 is another negative regulator involved in nutrient sensing. Thus, autophagy is suppressed by at least three parallel pathways, involving TORC1, PKA and Sch9, in nutrient-rich conditions.
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