Autophagy: process and function

doi:10.1101/GAD.1599207

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Autophagy: process and function

Journal Article•DOI•

Autophagy: process and function

Noboru Mizushima¹•Institutions (1)

Tokyo Medical and Dental University¹

15 Nov 2007-Genes & Development (Cold Spring Harbor Lab)-Vol. 21, Iss: 22, pp 2861-2873

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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Journal Article•DOI•

Hallmarks of cancer: the next generation.

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Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

ISREC¹, Massachusetts Institute of Technology²

04 Mar 2011-Cell

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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51,099 citations

Cites background from "Autophagy: process and function"

...AutophagyMediates Both TumorCell Survival andDeath Autophagy represents an important cell-physiologic response that, like apoptosis, normally operates at low, basal levels in cells but can be strongly induced in certain states of cellular stress, the most obvious of which is nutrient deficiency (Levine and Kroemer, 2008; Mizushima, 2007)....
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...…andDeath Autophagy represents an important cell-physiologic response that, like apoptosis, normally operates at low, basal levels in cells but can be strongly induced in certain states of cellular stress, the most obvious of which is nutrient deficiency (Levine and Kroemer, 2008; Mizushima, 2007)....
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...Like apoptosis, the autophagy machinery has both regulatory and effector components (Levine and Kroemer, 2008; Mizushima, 2007)....
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...Another interconnection between these two programs resides in the Beclin-1 protein, which has been shown by genetic studies to be necessary for induction of autophagy (Levine and Kroemer, 2008; Sinha and Levine, 2008; Mizushima, 2007)....
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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 "Autophagy: process and function"

...There are two ubiquitin-like systems that are key to autophagy [5,34] acting at the Atg5–Atg12 conjugation step and at the LC3 processing step (see below)....
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...In mammalian cells, phagophore membranes appear to initiate primarily from the ER [11,12] in dynamic equilibrium with other cytosolic membrane structures, such as the trans-Golgi and late endosomes [5,9,13] and possibly even derive membrane from the nuclear envelope under restricted conditions [14]....
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...When the autophagosome completes fusion of the expanding ends of the phagophore membrane, the next step towards maturation in this self-degradative process is fusion of the autophagosome with the specialized endosomal compartment that is the lysosome to form the ‘autolysosome’ [5]....
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...This phagophore expands to engulf intracellular cargo, such as protein aggregates, organelles and ribosomes, thereby sequestering the cargo in a double-membraned autophagosome [5]....
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...Lysosomal permeases and transporters export amino acids and other by-products of degradation back out to the cytoplasm, where they can be re-used for building macromolecules and for metabolism [5]....
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Journal Article•DOI•

TFEB links autophagy to lysosomal biogenesis.

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Carmine Settembre, Chiara Di Malta, Vinicia Assunta Polito¹, Vinicia Assunta Polito², Moises Garcia Arencibia³, Francesco Vetrini¹, Serkan Erdin², Serkan Erdin¹, Serpil Uckac Erdin¹, Serpil Uckac Erdin², Tuong Huynh², Tuong Huynh¹, Diego L. Medina, Pasqualina Colella, Marco Sardiello¹, Marco Sardiello², David C. Rubinsztein³, Andrea Ballabio - Show less +14 more•Institutions (3)

Baylor College of Medicine¹, Boston Children's Hospital², University of Cambridge³

17 Jun 2011-Science

TL;DR: A mitogen-activated protein kinase–dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles during starvation.

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Abstract: Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.

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2,409 citations

Journal Article•DOI•

Role of autophagy in cancer

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Robin Mathew¹, Vassiliki Karantza-Wadsworth¹, Eileen White•Institutions (1)

University of Medicine and Dentistry of New Jersey¹

01 Dec 2007-Nature Reviews Cancer

TL;DR: Evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.

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Abstract: Autophagy is a cellular degradation pathway for the clearance of damaged or superfluous proteins and organelles. The recycling of these intracellular constituents also serves as an alternative energy source during periods of metabolic stress to maintain homeostasis and viability. In tumour cells with defects in apoptosis, autophagy allows prolonged survival. Paradoxically, autophagy defects are associated with increased tumorigenesis, but the mechanism behind this has not been determined. Recent evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.

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2,016 citations

Cites background from "Autophagy: process and function"

...jpg" NDATA ITEM> ]> Autophagy is a cellular catabolic degradation response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolis...
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Journal Article•DOI•

Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy

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Nao Hosokawa¹, Taichi Hara¹, Takeshi Kaizuka¹, Chieko Kishi¹, Akito Takamura¹, Yutaka Miura¹, Shun-ichiro Iemura², Tohru Natsume², Kenji Takehana, Naoyuki Yamada³, Jun-Lin Guan⁴, Noriko Oshiro⁵, Noriko Oshiro⁶, Noboru Mizushima¹ - Show less +10 more•Institutions (6)

Tokyo Medical and Dental University¹, National Institute of Advanced Industrial Science and Technology², Ajinomoto³, University of Michigan⁴, Harvard University⁵, Kobe University⁶

01 Apr 2009-Molecular Biology of the Cell

TL;DR: A novel mammalian autophagy factor, Atg13, is reported, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200, and suggests that mTORC1 suppressesAutophagy through direct regulation of the approximately 3,MDa ULK 1-Atg13-FIP200 complex.

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Abstract: Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200. Atg13 localizes on the autophagic isolation membrane and is essential for autophagosome formation. In contrast to yeast counterparts, formation of the ULK1-Atg13-FIP200 complex is not altered by nutrient conditions. Importantly, mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. ULK1 is dephosphorylated by rapamycin treatment or starvation. These data suggest that mTORC1 suppresses autophagy through direct regulation of the approximately 3-MDa ULK1-Atg13-FIP200 complex.

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1,754 citations

Cites background from "Autophagy: process and function"

...Among the many factors that have thus far been reported (Codogno and Meijer, 2005; Meijer and Codogno, 2006; Mizushima, 2007), (m)TOR-mediated suppression appears to be a highly conserved, major regulatory mechanism....
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..., Mizushima, N., and Nakayama, K.I. (2005). Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle....
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...Macroautophagy (simply referred to as autophagy hereafter) is a major degradation system, by which cytoplasmic contents are degraded in the lysosomes (Klionsky, 2007; Mizushima, 2007; Levine and Kroemer, 2008; Mizushima et al., 2008)....
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References

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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 Mizushima¹, Noboru Mizushima², Takashi Ueno³, Akitsugu Yamamoto⁴, Takayoshi Kirisako¹, Takayoshi Kirisako⁵, Takeshi Noda¹, Takeshi Noda⁵, Eiki Kominami³, Yoshinori Ohsumi¹, Yoshinori Ohsumi⁵, 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

"Autophagy: process and function" refers background in this paper

...To date, only LC3, a mammalian homolog of Atg8, has been identified on the autophagosomal inner membrane (Kabeya et al. 2000)....
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Journal Article•DOI•

Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy

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Beth Levine¹, Daniel J. Klionsky²•Institutions (2)

Columbia University¹, University of Michigan²

01 Apr 2004-Developmental Cell

TL;DR: This review summarizes the current knowledge about the molecular machinery of autophagy and the role of the autophagic machinery in eukaryotic development and identifies a set of evolutionarily conserved genes that are essential forAutophagy.

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3,721 citations

"Autophagy: process and function" refers background in this paper

...During development, autophagy occurs in dying cells in various embryonic tissues (Levine and Klionsky 2004; Mizushima 2005)....
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...Autophagy is a general term for the degradation of cytoplasmic components within lysosomes (Cuervo 2004; Levine and Klionsky 2004; Shintani and Klionsky 2004; Klionsky 2005, 2007; Mizushima and Klionsky 2007)....
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...During development, autophagy occurs in dying cells in various embryonic tissues (Levine and Klionsky 2004; Mizushima 2005)....
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Journal Article•DOI•

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

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Taichi Hara¹, Kenji Nakamura², Makoto Matsui³, Makoto Matsui¹, Makoto Matsui⁴, Akitsugu Yamamoto⁵, Yohko Nakahara², Rika Suzuki-Migishima², Minesuke Yokoyama⁶, Kenji Mishima⁷, Ichiro Saito⁷, Hideyuki Okano⁸, Noboru Mizushima¹ - Show less +9 more•Institutions (8)

Institute of Medical Science¹, Mitsubishi², Graduate University for Advanced Studies³, National Institute for Basic Biology, Japan⁴, Nagahama Institute of Bio-Science and Technology⁵, Niigata University⁶, Tsurumi University⁷, Keio University⁸

15 Jun 2006-Nature

TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

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Abstract: Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

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3,684 citations

"Autophagy: process and function" refers background in this paper

...The most direct evidence is the accumulation of abnormal proteins and organelles in autophagy-deficient hepatocytes, neurons, and cardiomyocytes even in the absence of any disease-associated mutant protein (Komatsu et al. 2005, 2006; Hara et al. 2006; Nakai et al. 2007)....
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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

Book•

Isolation and characterization

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Kursad Turksen

01 Jan 2006

TL;DR: Animal Models and Therapy, Directed Differentiation and Characterization of Genetically Modified Embryonic Stem Cells for Therapy, and Use of Differentiating Embryonics Stem cells in the Parkinsonian Mouse Model are reviewed.

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Abstract: Isolation and Maintenance.- Isolation and Differentiation of Medaka Embryonic Stem Cells.- Maintenance of Chicken Embryonic Stem Cells In Vitro.- Derivation and Culture of Mouse Trophoblast Stem Cells In Vitro.- Derivation, Maintenance, and Characterization of Rat Embryonic Stem Cells In Vitro.- Derivation, Maintenance, and Induction of the Differentiation In Vitro of Equine Embryonic Stem Cells.- Generation and Characterization of Monkey Embryonic Stem Cells.- Derivation and Propagation of Embryonic Stem Cells in Serum- and Feeder-Free Culture.- Signaling in Embryonic Stem Cell Differentiation.- Internal Standards in Differentiating Embryonic Stem Cells In Vitro.- Matrix Assembly, Cell Polarization, and Cell Survival.- Phosphoinositides, Inositol Phosphates, and Phospholipase C in Embryonic Stem Cells.- Cripto Signaling in Differentiating Embryonic Stem Cells.- The Use of Embryonic Stem Cells to Study Hedgehog Signaling.- Transfection and Promoter Analysis in Embryonic Stem Cells.- SAGE Analysis to Identify Embryonic Stem Cell-Predominant Transcripts.- Utilization of Digital Differential Display to Identify Novel Targets of Oct3/4.- Gene Silencing Using RNA Interference in Embryonic Stem Cells.- Genetic Manipulation of Embryonic Stem Cells.- Efficient Transfer of HSV-1 Amplicon Vectors Into Embryonic Stem Cells and Their Derivatives.- Lentiviral Vector-Mediated Gene Transfer in Embryonic Stem Cells.- Use of the Cytomegalovirus Promoter for Transient and Stable Transgene Expression in Mouse Embryonic Stem Cells.- Use of Simian Immunodeficiency Virus Vectors for Simian Embryonic Stem Cells.- Generation of Green Fluorescent Protein-Expressing Monkey Embryonic Stem Cells.- DNA Damage Response and Mutagenesis in Mouse Embryonic Stem Cells.- Ultraviolet-Induced Apoptosis in Embryonic Stem Cells In Vitro.- Use of Embryonic Stem Cells in Pharmacological and Toxicological Screens.- Use of Differentiating Embryonic Stem Cells in Pharmacological Studies.- Embryonic Stem Cells as a Source of Differentiated Neural Cells for Pharmacological Screens.- Use of Murine Embryonic Stem Cells in Embryotoxicity Assays.- Use of Chemical Mutagenesis in Mouse Embryonic Stem Cells.- Epigenetic Analysis of Embryonic Stem Cells.- Nuclear Reprogramming of Somatic Nucleus Hybridized With Embryonic Stem Cells by Electrofusion.- Methylation in Embryonic Stem Cells In Vitro.- Tumor-Like Properties.- Identification of Genes Involved in Tumor-Like Properties of Embryonic Stem Cells.- In Vivo Tumor Formation From Primate Embryonic Stem Cells.- Animal Models and Therapy.- Directed Differentiation and Characterization of Genetically Modified Embryonic Stem Cells for Therapy.- Use of Differentiating Embryonic Stem Cells in the Parkinsonian Mouse Model.

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3,665 citations