Dynamics and diversity in autophagy mechanisms: lessons from yeast

Key Points

  • Eukaryotic cells have evolved a degradative pathway called autophagy that can deliver a large amount of cytoplasmic proteins and even whole organelles into lytic compartments, such as lysosomes in mammals or vacuoles in plant and yeast cells. Autophagy has vital roles in various physiological situations and is also involved in several pathological processes.

  • A number of physiological signals and stresses can induce autophagy. Following its induction, double membrane-bound vesicles called autophagosomes are newly formed in the cytoplasm to sequester materials (cargoes) to be degraded.

  • Two modes of cargo sequestration by autophagosomal membranes are suggested: non-selective (starvation-induced) autophagy, in which a portion of the cytoplasm is randomly engulfed, and selective autophagy, in which specific cargoes, such as toxic protein aggregates and superfluous or damaged organelles, are recognized and in many cases exclusively enwrapped by the membranes.

  • Studies in yeast have identified a unique subset of proteins called autophagy-related (Atg) proteins, which contain core components that are commonly required for membrane formation in all types of autophagy. These components constitute several subgroups, such as a protein kinase complex, a lipid kinase complex and two ubiquitin-like conjugation systems.

  • Atg proteins are concentrated at the site for membrane formation and organize a dynamic assembly called the preautophagosomal structure, in which Atg proteins specific for each type of autophagy (which differ in their induction signals and cargoes) are thought to serve as conductors that regulate the localization and activity of core machinery and determine the site and the mode of vesicle formation according to various situations.

Abstract

Autophagy is a fundamental function of eukaryotic cells and is well conserved from yeast to humans. The most remarkable feature of autophagy is the synthesis of double membrane-bound compartments that sequester materials to be degraded in lytic compartments, a process that seems to be mechanistically distinct from conventional membrane traffic. The discovery of autophagy in yeast and the genetic tractability of this organism have allowed us to identify genes that are responsible for this process, which has led to the explosive growth of this research field seen today. Analyses of autophagy-related (Atg) proteins have unveiled dynamic and diverse aspects of mechanisms that underlie membrane formation during autophagy.

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Figure 1: Autophagy in yeast.
Figure 2: Classification of Atg proteins.
Figure 3: The PAS as the assembly of Atg proteins.
Figure 4: The Atg1 subfamily.
Figure 5: Two PI3K complexes.
Figure 6: Two ubiquitin-like conjugation systems.
Figure 7: Model for the role of conductor proteins in PAS organization.

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Correspondence to Yoshinori Ohsumi.

Glossary

Macroautophagy

The sequestration of cytosolic components in autophagosomes and their subsequent degradation when autophagosomes fuse with lysosomes.

Autophagosome

A double membrane-bound vesicle that is formed during autophagy. The vesicle sequesters materials to be degraded and delivers them to the lysosome in mammals or the vacuole in yeasts and plants.

Ubiquitin–26S proteasome system

The system that degrades selected proteins that are first marked with ubiquitin chains and then degraded by the multi-catalytic proteinase complex, the proteasome.

Autophagic body

The inner membrane-bound structure of the autophagosome that is released into the vacuolar lumen by fusion of the autophagosomal outer membrane with the vacuolar membrane.

Vacuolar protein sorting

A pathway that mediates the selective transport of a subset of proteins from the late Golgi compartment to the vacuole through the endosome.

E1

An enzyme that activates ubiquitin and ubiquitin-like proteins using ATP and transfers them to E2 enzymes.

E2

An enzyme that receives ubiquitin and ubiquitin-like proteins from E1 enzymes and conjugates them to target molecules.

Deconjugation enzyme

An enzyme that cleaves the isopeptide bond (the amide bond between autophagyrelated protein 8 (Atg8) and phosphatidylethanolamine) formed in ubiquitin and ubiquitin-like protein conjugates.

Hemifusion

Fusion between outer leaflets of membranes while inner leaflets remain intact. This is regarded as a common intermediate state in biological membrane fusion events.

E3

An enzyme that stimulates the conjugation reaction by E2 enzymes and is also involved in the selection of target molecules.

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Nakatogawa, H., Suzuki, K., Kamada, Y. et al. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10, 458–467 (2009). https://doi.org/10.1038/nrm2708

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