Series |

Series on Autophagy

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.

Series Content

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.

Review Article | | Nature Cell Biology

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.

Review Article | | Nature Cell Biology

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.

Review Article | | Nature Cell Biology

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.

Review Article | | Nature Cell Biology

Editorial & Research Highlights

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.

Editorial | | Nature Cell Biology

Related Nature Cell Biology Research

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.

News & Views | | Nature Cell Biology

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.

News & Views | | Nature Cell Biology

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.

Review Article | | Nature Cell Biology

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.

News & Views | | Nature Cell Biology

Related Nature Journals Research

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Expanded polyglutamine (polyQ) tracts in different proteins are a common feature of many neurodegenerative diseases. Many normal proteins also carry these tracts, although their function remains unclear. David Rubinsztein and colleagues show that polyQ tracts in a normal ataxin protein have a role in the degradative process of autophagy. In this case, the polyQ domain allows ataxin 3 interaction with the autophagy mediator beclin 1. Ataxin 3 can thus deubiquitinate beclin 1, preventing its degradation by the proteasome and allowing it to initiate autophagy. The team not only demonstrate the relevance of their findings to the process of autophagy in neurons, but also show how, under disease conditions, the polyQ tracts in mutant proteins compete with those in ataxin 3 to prevent beclin 1 stabilization and so impair starvation-induced autophagy.

News & Views | | Nature

Expanded polyglutamine (polyQ) tracts in different proteins are a common feature of many neurodegenerative diseases. Many normal proteins also carry these tracts, although their function remains unclear. David Rubinsztein and colleagues show that polyQ tracts in a normal ataxin protein have a role in the degradative process of autophagy. In this case, the polyQ domain allows ataxin 3 interaction with the autophagy mediator beclin 1. Ataxin 3 can thus deubiquitinate beclin 1, preventing its degradation by the proteasome and allowing it to initiate autophagy. The team not only demonstrate the relevance of their findings to the process of autophagy in neurons, but also show how, under disease conditions, the polyQ tracts in mutant proteins compete with those in ataxin 3 to prevent beclin 1 stabilization and so impair starvation-induced autophagy.

Letter | | Nature

Ageing haematopoietic stem cells (HSCs) are not able to regenerate blood cells as well as their younger counterparts, and show bias towards particular lineages. But autophagy has previously been shown to protect HSCs from the effects of metabolic stress. Here Emmanuelle Passegué and colleagues find that loss of autophagy in HSCs increases the accumulation of mitochondria and raises the metabolic state of HSCs, disturbing their abilities for self-renewal and regeneration. This behaviour is similar to that observed in old HSCs, although about one-third of old HSCs still have a high level of autophagy and a low metabolic state to help them maintain their regenerative capacity.

Article | | Nature

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.

Article | Open Access | | Nature Communications

Using a Drosophila model of tumorigenesis, Tor Erik Rusten and colleagues show that tumour cells under stress induce autophagy in their microenvironment, by oncogene and inflammatory signalling, as a way of generating nutrients for tumour growth and dissemination. These findings illustrate the importance of tumour-environmental crosstalk and shed light on the potential of systemic autophagy as a targetable process in cancer.

Letter | | Nature

Cancer cells generally have metabolic needs that differ from those of neighbouring normal cells, and hence display rewired metabolic networks. Cristovão Sousa et al. show that, in pancreatic cancers, stellate cells in the tumour environment supply cancer cells with the amino acid alanine as the carbon needed for anabolic processes when other sources are scarce. Tumour cells in turn stimulate autophagy in stellate cells, which is needed for alanine secretion. This cross-talk allows pancreatic cancer cells to fulfil their metabolic requirements in an environment lacking in other essential nutrients.

Letter | | Nature

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Cells can respond to nutrient starvation with the process of autophagy, which allows cytoplasmic proteins and organelles to be degraded by the lysosome. Here, Sung Hee Baek and colleagues investigate the nuclear events involved in regulating autophagy and identify the enzyme CARM1 (co-activator-associated arginine methyltransferase 1) as a transcriptional co-activator for the autophagy transcription factor TFEB. Levels of CARM1 are repressed by a SKP2-containing E3 ubiquitin ligase SCF and are increased during autophagy induction after nutrient starvation.

Letter | | Nature

Jennifer Martinez et al. provide evidence that defects in LC3-associated phagocytosis in mice result in a condition resembling the autoimmune disease systemic lupus erythematosus. Dying cells are engulfed but not degraded in mice deficient in LC3-associated phagocytosis, resulting in elevated serum anti-DNA antibodies, inflammatory cytokines, and kidney disease. The effect is independent of canonical autophagy. These findings suggest a link between the clearance of dying cells, autophagic processes, and inflammation in the control of systemic lupus erythematosus.

Letter | | Nature

The regenerative properties of muscle stem cells decline with age, as they enter an irreversible senescence state. Pura Muñoz-Cánoves and colleagues show that before entering senescence, mouse muscle stem cells preserve their repair properties by returning to a reversible quiescence state in an autophagy-dependent manner. Preventing autophagy in young satellite stem cells promotes their entry into senescence and correlates with an increase in mitochondrial dysfunction and oxidative stress. Conversely, promoting autophagy in old satellite cells reverses senescence and restores their regenerative properties in an injury model.

Article | | Nature

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.

Review Article | | Nature Reviews Cancer