Autophagosome biogenesis: From membrane growth to closure

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Abstract

Melia et al. review the molecular mechanisms and membrane modeling events underlying autophagosome biogenesis.

Abstract

Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes to form a double-membrane vesicle (an autophagosome). This process has remained enigmatic since its initial discovery >50 yr ago, but our understanding of the mechanisms involved in autophagosome biogenesis has increased substantially during the last 20 yr. Several key questions do remain open, however, including, What determines the site of autophagosome nucleation? What is the origin and lipid composition of the autophagosome membrane? How is cargo sequestration regulated under nonselective and selective types of autophagy? This review provides key insight into the core molecular mechanisms underlying autophagosome biogenesis, with a specific emphasis on membrane modeling events, and highlights recent conceptual advances in the field.

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Most cited references 208

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AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

Joungmok Kim, Mondira Kundu, Benoit Viollet … (2011)

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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The role of Atg proteins in autophagosome formation.

Noboru Mizushima, Tamotsu Yoshimori, Yoshinori Ohsumi (2011)

Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.

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Biological Functions of Autophagy Genes: A Disease Perspective

Beth Levine, Guido Kroemer (2019)

The lysosomal degradation pathway of autophagy plays a fundamental role in cellular, tissue, and organismal homeostasis and is mediated by evolutionarily conserved autophagy-related (ATG) genes. Definitive etiological links exist between mutations in genes that control autophagy and human disease, especially neurodegenerative, inflammatory disorders and cancer. Autophagy selectively targets dysfunctional organelles, intracellular microbes, and pathogenic proteins, and deficiencies in these processes may lead to disease. Moreover, ATG genes have diverse physiologically important roles in other membrane-trafficking and signaling pathways. This Review discusses the biological functions of autophagy genes from the perspective of understanding-and potentially reversing-the pathophysiology of human disease and aging.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Biol

Journal ID (iso-abbrev): J. Cell Biol

Journal ID (publisher-id): jcb

Title: The Journal of Cell Biology

Publisher: Rockefeller University Press

ISSN (Print): 0021-9525

ISSN (Electronic): 1540-8140

Publication date Collection: 01 June 2020

Publication date (Electronic): 01 May 2020

Volume: 219

Issue: 6

Electronic Location Identifier: e202002085

Affiliations

[1 ]Department of Cell Biology, Yale University School of Medicine, New Haven, CT

[2 ]Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

Author notes

Correspondence to Anne Simonsen: anne.simonsen@ 123456medisin.uio.no

Author information

Thomas J. Melia https://orcid.org/0000-0002-5798-4624

Alf H. Lystad https://orcid.org/0000-0002-5606-3276

Anne Simonsen https://orcid.org/0000-0003-4711-7057

Article

Publisher ID: jcb.202002085

DOI: 10.1083/jcb.202002085

PMC ID: 7265318

PubMed ID: 32357219

SO-VID: 4fbc34b2-6995-4e5d-b1c1-5ba8ae6ac571

License:

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

History

Date received : 13 February 2020

Date revision received : 04 April 2020

Date accepted : 06 April 2020

Page count

Pages: 18

Funding

Funded by: Research Council of Norway, DOI http://dx.doi.org/10.13039/501100005416;

Award ID: 221831

Funded by: Centres of Excellence;

Award ID: 262652

Funded by: Norwegian Cancer Society, DOI http://doi.org/10.13039/100008730;

Award ID: 171318

Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;

Award ID: GM100930

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