Key Points
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Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles.
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It begins when double-membraned autophagosomes engulf portions of cytoplasm, which is followed by the fusion of these vesicles with lysosomes and degradation of the autophagic contents.
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In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders.
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This Review provides an overview of the mechanisms involved in autophagy, and briefly reviews the various signalling pathways that control the process, as a backdrop for considering potential targets that may be druggable.
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We consider the roles of autophagy in different diseases, focusing on metabolic diseases, neurodegenerative diseases, cancers, infectious diseases and immunity.
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Autophagy may be inhibited or activated during different diseases, and the possible consequences of these effects are explored.
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We discuss disease states in which autophagy upregulation or inhibition may be beneficial.
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Candidate therapeutic possibilities for autophagy inhibition, autophagy upregulation and modulation of the clearance of selective autophagy substrates are also considered, and we provide an overview of the different pharmacological agents that are currently available as potential drugs and chemical probes.
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Last, we consider some possible future directions as well as caveats for various therapeutic approaches involving autophagy modulation.
Abstract
Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation.
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Acknowledgements
D.C.R. is supported by the Wellcome Trust (Principal Fellowship), a Wellcome Trust/Medical Research Council Strategic Award on Neurodegenerative Diseases, the UK Medical Research Council and the National Institute for Health Research Biomedical Research Unit in Dementia at Addenbrooke's Hospital, Cambridge, UK. B.L. is supported by US National Institutes of Health (NIH) grants RO1 CA109618 and U54AI057156. P.C. is supported by INSERM, Université Paris-Sud 11, Agence Nationale pour la Recherche and Institut National du Cancer. The authors are grateful to F. Menzies and W. Hochfeld for technical assistance.
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David C. Rubinsztein has received honorarium for speaking at a symposium organized by Pfizer, and received partial funding for his Ph.D. from Lilly. Patrice Codogno and Beth Levine declare no competing financial interests.
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Glossary
- Autophagosomes
-
Double-membrane vesicles that engulf cytoplasmic contents for delivery to the lysosome.
- Phagophore
-
A cup-shaped, double-membrane autophagic precursor structure.
- Microtubule organizing centre
-
A structure near the nucleus of eukaryotic cells, from which microtubules emerge.
- Class III phosphoinositide 3-kinases
-
(PI3Ks; also known as PIK3C3 or VPS34). Enzymes that produce phosphatidylinositol-3-phosphate (PtdIns3P).
- SNAREs
-
Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptors; these molecules enable vesicle fusion events.
- Selective autophagy
-
Autophagic processes involving the preferential recruitment of specific substrates, in contrast to random bulk cytoplasmic sequestration.
- Gluconeogenesis
-
A metabolic pathway that generates glucose from non-carbohydrate carbon sources, thus preventing blood sugar levels from becoming too low.
- Pancreatic β-cells
-
Insulin-producing cells in the pancreas.
- Dynactin
-
A component of the dynein motor complex.
- Tumour suppressor genes
-
Genes that protect cells from one of the steps along the pathway to cancer.
- Autophagy adaptor proteins
-
Proteins that mediate selective autophagy: for example, ubiquitin-binding protein p62 (also known as sequestosome 1).
- Short hairpin RNA
-
Small RNAs that form hairpins that can induce sequence-specific silencing in mammalian cells through RNA interference.
- Lysosomotropic agents
-
Compounds that accumulate preferentially in lysosomes; many weak bases are lysosomotropic agents.
- Encephalitis
-
Inflammation in the brain.
- Interferon
-
A type of protein made and released by host cells in response to bacteria, viruses and tumour cells.
- MHC class II
-
Major histocompatibility complex (MHC) class II; molecules that are found on antigen-presenting cells and lymphocytes. The antigens presented by MHC class II molecules are derived from extracellular proteins.
- MHC class I
-
Major histocompatibility complex (MHC) class I; molecules that are found on the surfaces of all nucleated cells and present peptides derived from cytosolic proteins.
- Paneth cells
-
Cells in the small intestine that assist in antibacterial defence.
- Autophagosome maturation
-
The processes occurring after the completion of autophagosome closure that enable the delivery of the autophagosome to — and its degradation in — the lysosome.
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Rubinsztein, D., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 11, 709–730 (2012). https://doi.org/10.1038/nrd3802
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DOI: https://doi.org/10.1038/nrd3802
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