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Autophagy is a catabolic process through which cells replenish their macromolecular stores in response to nutrient deficiency, and also maintain homeostatic health and survival by degrading damaged proteins and organelles. Autophagy has emerged as a fundamental and conserved cellular mechanism with complex roles in health and disease. Nature Cell Biology presents a series of specially commissioned articles that will discuss recent advances and outstanding questions driving this expanding and diverse field. An accompanying online library contains research and Review articles on this topic published in the past two years by Nature Cell Biology and the Nature journals.
A history of autophagy. In this Perspective, Mizushima describes the leaps and bounds in the history of autophagy and discusses unanswered questions driving the field forward.
In this Review Article, Klionsky and co-authors discuss selective autophagy pathways that degrade unwanted cytosolic components and organelles, and how these pathways require ligand receptors and scaffold proteins for cargo specificity.
Autophagy and cancer: In this Review, Galluzzi and colleagues discuss the cellular and molecular mechanisms whereby autophagy functions in multiple aspects of malignant disease, including cancer initiation, progression and responses to therapy.
In this Review, Tavernarakis and colleagues describe recent advances in delineating the molecular mechanisms that mediate mitophagy, and discuss the complex roles of this pathway in physiological and pathological contexts.
In this Review, Doherty and Baehrecke discuss the multiple roles of autophagy during cell survival and cell death. They cover the interplay between autophagy, apoptosis and necrosis, as well as engulfment and inflammation.
In this Review, Leidal et al. discuss the role and regulation of autophagy in aging. They cover how autophagy promotes longevity and restricts cellular damage, and discuss autophagy modulators for the potential treatment of age-related diseases.
Autophagy is a cellular degradation and recycling process with complex roles in health and disease and emerging relevance to translational research. In this issue, we launch a Series of commissioned articles that will discuss recent advances and outstanding questions driving this rapidly expanding and diverse field.
An and Harper quantify ribophagy in mammalian cells and show that nutrient-deprivation-induced ribophagy is independent of the ATG8 conjugation system, whereas proteotoxic stress-induced ribophagy requires ATG5 and VPS34.
Selective autophagy is important for controlled degradation of cellular components. However, a selective autophagic degradation mechanism for ribosomes in mammals has remained unclear. A study now describes non-selective and selective ribosome degradation and a significant role for ‘bystander’ non-selective autophagy.
Sato et al. identify ALLO-1 as an autophagy receptor required for paternal organelle clearance in Caenorhabditis elegans, and this process is dependent on ALLO-1 phosphorylation by the TBK1 family kinase IKKE-1.
Lu et al. show that the choice between proteasomal degradation and selective autophagy is independent of the ubiquitin-binding properties of the receptors but largely determined by oligomerization potential.
Fumagalli et al. show that Sec62 delivers ER components to the autolysosome for clearance by acting as a receptor for autophagy protein LC3-II. This identifies Sec62 as a critical factor for selective ER turnover.
The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, and its size needs to be carefully controlled. Downsizing the ER by autophagy is now shown to involve Sec62, a protein that also helps to build up the organelle. This link suggests a molecular switch for ER size control.
De Leo et al. identify a lysosomal response to autophagic cargo during lysosome–autophagosome fusion that involves TLR9 activation and OCRL recruitment, and leads to a regulated local increase in PtdIns(4,5)P2, which is necessary for a normal autophagic flux.
Jiang et al. show that Disabled-2 (Dab2) regulates the switch between autophagy and apoptosis in TGB-β-treated cells, through regulation of the Beclin-1–Vps34 interaction.
In this Review, Prinz and co-authors discuss the role of the endoplasmic reticulum (ER) in the de novo generation of peroxisomes, lipid droplets and omegasomes, and how this requires subdomains with specific protein and lipid compositions.
Orhon et al. report that primary-cilium-mediated fluid flow sensing triggers autophagy through LKB1–AMPK–mTOR signalling, and thereby controls the volume of kidney epithelial cells.
The primary cilium and the process of autophagy are thought to be in a functionally reciprocal relationship. In further support of this link, fluid flow sensing by the primary cilium is now shown to induce autophagy, which in turn regulates the volume of kidney epithelial cells.
Green and colleagues characterize LC3-associated phagocytosis as a process that depends on Rubicon, Beclin-1, UVRAG and VPS34 but not on canonical autophagy proteins.
Phagocytic cells engulf their prey into vesicular structures called phagosomes, of which a certain proportion becomes demarcated for enhanced maturation by a process called LC3-associated phagocytosis (LAP). Light has now been shed on the molecular requirements of LAP, establishing a central role for the protein Rubicon in the immune response to Aspergillus fumigatus.
Ding and colleagues show that somatic cell reprogramming does not depend on Atg5-dependent canonical autophagy, but requires mitochondrial clearance in an Atg5-independent manner downstream of AMPK.
The survival of hematopoietic stem cells requires tight regulation of mitophagy. Lin and colleagues show that Atad3a regulates mitophagy in these cells by sequestering the mitophagy initiator Pink1 and directing its import via the mitochondrial Tom40–Tim23 complex.
Various intracellular pathogens attempt to hide from innate cytosolic sensors by forming vacuoles. Yamamoto and colleagues show that the autophagy-related protein Gate-16, which is induced by interferon-γ, is required for noncanonical autophagy to control infection by Toxoplasma gondii.
Soluble misfolded proteins that fail to be degraded by the ubiquitin proteasome system (UPS) are redirected to autophagy via specific adaptors, such as p62. Here the authors show that p62 recognises N-degrons in these proteins, acting as a N-recognin from the proteolytic N-end rule pathway, and targets these cargos to autophagosomal degradation.
During autophagy, AMPK and mTOR associate with ULK1 and regulate phosphatidylinositol 3-phosphate (PtdIns3P) production that mediates autophagosome formation via WIPI proteins. Here the authors show WIPI3 and WIPI4 have a scaffolding function upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes.
Mutant proteins that contain stretches called polyQ repeats can misfold or form aggregates linked to neurodegeneration. It emerges that some polyQ-containing proteins regulate a process that degrades misfolded proteins. See Letter p.108
The polyglutamine domain in ataxin 3, which is expanded in spinocerebellar ataxia type 3, allows normal ataxin 3 to interact with and deubiquitinate beclin 1 and thereby to promote autophagy.
Loss of autophagy increases the accumulation of mitochondria and the respiration status of haematopoietic stem cells, which perturbs their self-renewal and regeneration activities, and promotes cellular aging.
Damaged mitochondria are normally cleared through canonical and alternative autophagy pathways. Here, the authors report that mitochondria can be cleared through an autophagy-independent endosomal-lysosomal pathway that depends on Parkin-dependent sequestration of mitochondria in Rab5-positive early endosomes.
During early-stage tumour growth in Drosphila, tumour cells acquire necessary nutrients by triggering autophagy in surrounding cells in the tumour microenvironment.
Spermidine, a naturally occurring polyamine, extends the lifespan of mice and is cardioprotective in both aged mice and hypertensive rats. In humans, high dietary spermidine intake is associated with reduced blood pressure and a lower incidence of cardiovascular disease.
Pancreatic adenocarcinoma cells drive autophagy in tumour microenvironment-associated stellate cells, which release alanine that is used by the cancer cells as a carbon source for a variety of metabolic processes in an otherwise nutrient-poor environment.
The naturally occurring compound urolithin A has been found to promote mitophagy, thereby increasing lifespan in worms and improving skeletal muscle activity in rodents.
The ULK1 complex is required during autophagosome nucleation, but where autophagic membranes initiate is unknown. Here the authors use super-resolution microscopy to propose that autophagosomes originate from tubulovesicular structures in the ER that align with ATG9 vesicles and recruit ULK1.
Reactive oxygen species (ROS) damage cell components, necessitating their clearance through autophagy. Here, the authors show that ROS can induce autophagy by triggering TRPML1 to release Ca2+from the lysosomal lumen, in turn activating the autophagy and lysosomal biogenesis regulator TFEB.
An investigation into the nuclear events involved in autophagy regulation identifies the histone arginine methyltransferase CARM1 as a transcriptional co-activator of transcription factor TFEB; CARM1 levels are decreased by the SKP2-containing E3 ubiquitin ligase and increased during autophagy induction after nutrient starvation.
Defects in LC3-associated phagocytosis in mice are shown to result in systemic lupus erythematosus-like disease; dying cells are engulfed but not degraded in LAP-deficient mice, resulting in increased serum levels of autoantibodies and inflammatory cytokines, and evidence of kidney disease.
The regenerative properties of muscle stem cells decline with age as the stem cells enter an irreversible state of senescence; a study of mouse muscle stem cells reveals that entry into senescence is an autophagy-dependent process and promoting autophagy in old satellite cells can reverse senescence and restore their regenerative properties in an injury model.
This protocol from Wang et al. describes a pulse–chase method to investigate autophagic protein degradation through click labeling of long-lived proteins. This is a safer alternative to similar classic methods that use radioactive labeling.
Sun et al. describe how to image and quantify mitophagy in both living cells and tissues, using the pH-sensitive fluorescent reporter mt-Keima. This protocol provides information for analysis by both confocal and super-resolution microscopy.
Correia-Melo et al. describe a protocol to generate and maintain mitochondria-depleted mammalian cell lines. These cells can be used to investigate the role of mitochondria in various cellular processes such as cell death and senescence.
Autophagy is a process that delivers cytoplasmic components to lysosomes for degradation. This Review discusses clinical interventions to target autophagy in cancer and explains how understanding the context-dependent role of autophagy in cancer should dictate future clinical trial design.