Autophagy

Autophagy can have two functions in cancer: it can be tumour suppressive or tumour promoting. Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved is important for the use of autophagy-based therapeutics.

Data suggest that autophagy, a process normally associated with cell survival, also promotes cell death, depending on the stimulus or cell type. Thorburn and colleagues find that differences in basal autophagy levels in cells determine survival or death in response to death receptor activation, through modulation of Fap-1 degradation.

Reactive oxygen species inhibit mTORC1 signalling, but the subcellular localization of this event has been unclear. Walker and colleagues show that the tuberous sclerosis complex (TSC) is located at the peroxisome, where it functions as a Rheb GTPase-activator protein to suppress mTORC1 and induce autophagy. They also show that disease-associated mutations in TCS2 display impaired peroxisome localization and mTORC1 repression.

The protein kinase ULK1 regulates autophagy induction but its mode of action is poorly understood. Guan and colleagues show that following nutrient starvation, ULK1-mediated phosphorylation of Beclin-1 is required for the activation of VPS34 lipid kinase within the autophagy complex ATG1–VPS34–Beclin-1. They also find that during starvation, the inhibitory effect of mTOR on ULK1 is relieved to increase the phosphorylation of Beclin-1.

Autophagy, which is believed to be an Atg7- and Atg3-dependent process, is known to be involved in animal development. Baehrecke and colleagues show that autophagy drives the controlled degradation of the developing Drosophila midgut. Interestingly, this process is Atg7- and Atg3-independent, and instead requires the E1-activating enzyme Uba1 for programmed reduction of cell size in the midgut.

mTOR inhibition induces autophage-mediated degradation but few mTOR targets in the process have been identified so far. Cecconi and colleagues show that mTOR inhibits the autophagy regulator AMBRA1 by phosphorylation. Following autophagy induction, AMBRA1 is dephosphorylated and interacts with the E3 ligase TRAF6 to stabilize and activate ULK1 (a kinase required for autophagy) through its ubiquitylation.

Autophagy is an important cellular recycling mechanism that can be either tumor-promoting or tumor-suppressive and represents a novel anti-cancer target. In this article, Janku and colleagues explain the rational behind targeting autophagy for the development of anticancer therapy and discuss drugs that either inhibit or activate autophagy.

In this Review—intended as an introduction to the topic of hepatic autophagy for clinical scientists—the authors describe the different types of hepatic autophagy, their role in maintaining homeostasis in a healthy liver and the contribution of autophagic malfunction to liver disease.

It is increasingly understood that autophagy is an ancient defence mechanism that has become incorporated into numerous immunological pathways. As discussed in this Review, its immunological roles include the elimination of microorganisms, the control of inflammation, the regulation of antigen presentation and lymphocyte homeostasis, and the secretion of immune mediators.

Autophagy not only degrades components of host cells but can also target intracellular bacteria and thus contribute to host defences. Here, Huang and Brumell discuss the canonical and selective pathways of antibacterial autophagy, as well as the ways in which bacteria can escape from them and sometimes even use them to promote infection.

Autophagosome biogenesis starts at the isolation membrane (also called the phagophore). Our understanding of the molecular processes that initiate the isolation membrane, the membrane sources from which this membrane originates and how it is expanded to the autophagosome membrane by autophagy-related (ATG) proteins and the vesicular trafficking machinery, is increasing.

Autophagy was thought to be a purely cytosolic event. However, recent data highlight a role for the nucleus in autophagy regulation, showing that a complex network of histone modifications, microRNAs and transcription factors also control this process.

Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively. It is now clear that these processes often occur sequentially, and that crosstalk between the signalling pathways regulating them generally enables autophagy to block the induction of apoptosis, whereas apoptosis-associated caspase activation shuts off autophagy.

Defects in autophagy—a process that enables the degradation of unwanted or damaged intracellular proteins and organelles—are associated with the accumulation of aggregate-prone proteins. Defects in neuronal autophagy may have a role in neurodegenerative disease that are associated with aberrant protein accumulation, such as Alzheimer disease and Parkinson disease. Rubinsztein and Harris discuss how defects in autophagic pathways might cause these diseases and highlight how autophagy-modulating drugs might be used as therapy.

Cartilage damage frequently occurs during aging, and represents a known risk factor for the development of osteoarthritis (OA). In this Review, the authors discuss the homeostatic processes that maintain cartilage, how these become defective with age, and how these malfunctions can contribute to the development of disease. The tantalizing prospect of augmenting homeostatic mechanisms as a new therapeutic strategy against joint aging and OA is introduced.

Programmed cell death (PCD) is a vital process in the development and maintenance of immune cell populations. In this Review, the authors describe some of the major mechanisms of apoptosis, the role of defective PCD in autoimmunity, and the potential of therapeutic targeting of apoptosis pathways in patients with rheumatic diseases.

A biochemical approach is used to understand how the ULK1 complex integrates signals from ATG proteins during autophagy. The interaction between ULK1-associated protein FIP200 and ATG16L1 of the ATG5 complex is revealed. This interaction is important for autophagy induced by amino acid starvation but not by glucose deprivation.

The ATG12~ATG5 conjugate promotes the transfer of the ubiquitin-like protein LC3 to phosphatidylethanolamine (PE), a modification required for autophagosome formation. Structural and biochemical analyses reveal the determinants for ATG12~ATG5 binding to ATG16 and the E3 ligase ATG3, and indicate how the conjugate stimulates PE–LC3 formation.

An early step in the autophagy process is the conjugation of the ubiquitin-like proteins (UBLs) Atg8 and Atg12 to their targets. Structural and functional experiments reveal how the autophagy E1 Atg7 uses a trans mechanism to catalyze the charging of the autophagy UBLs onto their respective carrier E2 proteins, Atg3 and Atg10.

The enzymes involved in autophagy-related UBL conjugation bear only passing resemblance to their counterparts in the better-known UBL conjugation pathways. New structural work provides insight into the mechanism by which the UBL proteins Atg8 and Atg12 are correctly charged by a single activating enzyme, Atg7, then transferred onto their cognate E2 proteins, Atg3 and Atg10, respectively.