Dynamics and diversity in autophagy mechanisms: lessons from yeast

doi:10.1038/NRM2708

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Dynamics and diversity in autophagy mechanisms: lessons from yeast

Journal Article•DOI•

Dynamics and diversity in autophagy mechanisms: lessons from yeast

Hitoshi Nakatogawa¹, Kuninori Suzuki¹, Yoshiaki Kamada², Yoshinori Ohsumi¹•Institutions (2)

Tokyo Institute of Technology¹, National Institute for Basic Biology, Japan²

01 Jul 2009-Nature Reviews Molecular Cell Biology (Nature Publishing Group)-Vol. 10, Iss: 7, pp 458-467

TL;DR: 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.

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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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Figures (7)

Table 1. Subgroups of Atg proteins required for starvation-induced autophagy subgroup and component known or putative function Atg1 kinase and its regulators triggering and regulating PAS assembly of other proteins

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Journal Article•DOI•

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

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Joungmok Kim¹, Mondira Kundu², Benoit Viollet³, Kun-Liang Guan¹•Institutions (3)

University of California, San Diego¹, St. Jude Children's Research Hospital², Paris Descartes University³

01 Feb 2011-Nature Cell Biology

TL;DR: A molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1, is demonstrated and a signalling mechanism for UlK1 regulation and autophagic induction in response to nutrient signalling is revealed.

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Abstract: Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

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5,314 citations

Cites background from "Dynamics and diversity in autophagy..."

...Genetic studies in Saccharomyces cerevisiae have defined the autophagy machiner...
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Journal Article•DOI•

Autophagy: Renovation of Cells and Tissues

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Noboru Mizushima¹, Masaaki Komatsu²•Institutions (2)

Tokyo Medical and Dental University¹, Institute of Medical Science²

11 Nov 2011-Cell

TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.

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4,529 citations

Cites background from "Dynamics and diversity in autophagy..."

...Figure 2 summarizes their functional steps in mammalian cells, and more details for this process are described extensively elsewhere (Chen and Klionsky, 2011; Mizushima et al., 2011; Nakatogawa et al., 2009)....
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...In the 1990s, genetic studies in yeast identified a series of autophagy-related (ATG) genes (Klionsky et al., 2003; Nakatogawa et al., 2009)....
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...Among the 35 Atg proteins thus far identified in yeast, Atg1–10, 12–14, 16, and 18 are the ‘‘core Atg proteins’’ (Nakatogawa et al., 2009)....
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...The core Atg proteins are shared by other autophagy-related pathways, such as pexophagy (autophagic degradation of the peroxisome) and the cytoplasm-to-vacuole targeting pathway, which have been discussed in more detail in other reviews (Chen and Klionsky, 2011; Nakatogawa et al., 2009; Youle and Narendra, 2011)....
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...…are shared by other autophagy-related pathways, such as pexophagy (autophagic degradation of the peroxisome) and the cytoplasm-to-vacuole targeting pathway, which have been discussed in more detail in other reviews (Chen and Klionsky, 2011; Nakatogawa et al., 2009; Youle and Narendra, 2011)....
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Journal Article•DOI•

Autophagy in immunity and inflammation

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Beth Levine¹, Noboru Mizushima², Herbert W. Virgin³•Institutions (3)

University of Texas Southwestern Medical Center¹, Tokyo Medical and Dental University², Washington University in St. Louis³

20 Jan 2011-Nature

TL;DR: A crucial role is revealed for the autophagy pathway and proteins in immunity and inflammation, and they balance the beneficial and detrimental effects of immunity andinflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

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Abstract: Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.

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2,757 citations

Cites background from "Dynamics and diversity in autophagy..."

...Nonetheless, the molecular dissection of autophagy membrane dynamics, stimulated by the discovery of ATG (autophagy-related) genes in yeast 9 , has shed considerable light on this topic (Table 1) ....
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...The second is the phosphatidylethanolamine (PE)-conjugated ATG8 homologues -LC3, GATE16 and GABARAP -which are produced by the ATG7 and ATG3 (E2-like) enzymes 9, 20 ....
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Journal Article•DOI•

Mechanisms of mitophagy

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Richard J. Youle¹, Derek P. Narendra¹, Derek P. Narendra²•Institutions (2)

National Institutes of Health¹, Medical Research Council²

01 Jan 2011-Nature Reviews Molecular Cell Biology

TL;DR: Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L).

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Abstract: Mitophagy is the selective elimination of mitochondria through autophagy Recent studies have uncovered the molecular mechanisms mediating mitophagy in yeast and mammalian cells and have revealed that the dysregulation of one of these mechanisms — the PINK1–parkin-mediated signalling pathway — may contribute to Parkinson's disease

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2,608 citations

Journal Article•DOI•

Autophagy: cellular and molecular mechanisms.

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Danielle Glick¹, Sandra Barth¹, Kay F. Macleod¹•Institutions (1)

University of Chicago¹

01 May 2010-The Journal of Pathology

TL;DR: This review summarizes the most up‐to‐date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.

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Abstract: Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.

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2,594 citations

Cites background from "Dynamics and diversity in autophagy..."

...Although the importance of autophagy is well recognized in mammalian systems, many of the mechanistic breakthroughs in delineating how autophagy is regulated and executed at the molecular level have been made in yeast (Saccharomyces cerevisiae) [3,7]....
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...Both peroxisomes and ribosomes are selectively eliminated via autophagy in yeast [3]....
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...Currently, 32 different autophagyrelated genes (Atg) have been identified by genetic screening in yeast and, significantly, many of these genes are conserved in slime mould, plants, worms, flies and mammals, emphasizing the importance of the autophagic process in responses to starvation across phylogeny [3]....
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Journal Article•DOI•

LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing

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Yukiko Kabeya¹, Noboru Mizushima², Noboru Mizushima¹, Takashi Ueno³, Akitsugu Yamamoto⁴, Takayoshi Kirisako¹, Takayoshi Kirisako⁵, Takeshi Noda⁵, Takeshi Noda¹, Eiki Kominami³, Yoshinori Ohsumi⁵, Yoshinori Ohsumi¹, Tamotsu Yoshimori¹, Tamotsu Yoshimori⁵ - Show less +10 more•Institutions (5)

National Institute for Basic Biology, Japan¹, National Presto Industries², Juntendo University³, Kansai Medical University⁴, Graduate University for Advanced Studies⁵

01 Nov 2000-The EMBO Journal

TL;DR: It is demonstrated that the rat microtubule‐associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing.

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Abstract: Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.

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6,244 citations

Journal Article•DOI•

Autophagy fights disease through cellular self-digestion

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Noboru Mizushima¹, Beth Levine², Ana Maria Cuervo³, Daniel J. Klionsky⁴•Institutions (4)

Tokyo Medical and Dental University¹, University of Texas at Dallas², Yeshiva University³, University of Michigan⁴

28 Feb 2008-Nature

TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.

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Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

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5,831 citations

Journal Article•DOI•

TOR signaling in growth and metabolism.

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Stephan Wullschleger¹, Robbie Loewith², Michael N. Hall¹•Institutions (2)

University of Basel¹, University of Geneva²

10 Feb 2006-Cell

TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.

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5,553 citations

Journal Article•DOI•

p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy

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Serhiy Pankiv¹, Terje Høyvarde Clausen¹, Trond Lamark¹, Andreas Brech², Jack-Ansgar Bruun¹, Heidi Outzen¹, Aud Øvervatn¹, Geir Bjørkøy¹, Terje Johansen¹ - Show less +5 more•Institutions (2)

University of Tromsø¹, Oslo University Hospital²

17 Aug 2007-Journal of Biological Chemistry

TL;DR: It is demonstrated that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation and p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.

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3,676 citations

Journal Article•DOI•

Autophagy: process and function

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Noboru Mizushima¹•Institutions (1)

Tokyo Medical and Dental University¹

15 Nov 2007-Genes & Development

TL;DR: In this review, the process of autophagy is summarized, and the role of autophileagy is discussed in a process-based manner.

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Abstract: Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex. Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. In this review, the process of autophagy is summarized, and the role of autophagy is discussed in a process-based manner.

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3,527 citations

"Dynamics and diversity in autophagy..." refers background in this paper

...Atg18 can bind to both PtdIns3P and PtdIns(3,5)P2 (REFS 53,54), and is therefore a potent candidate for the effector of these molecules....
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...Whereas the autophagosome formation function of Atg18 involves PtdIns3P, the regulatory function in vacuole morphology depends on PtdIns(3,5)P2 (REFS 50,55)....
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...A portion of Atg18 forms a complex with Atg2 and functions in autophagosome formation27,50, whereas this protein also regulates the size of the vacuole and PtdIns(3,5)P2 homeostasis in complex with other proteins53,55 (FIG....
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