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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.
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.