2016 Nobel Prize in Physiology or Medicine

Studies of autophagy in yeast have identified a family of autophagy-related (Atg) proteins, which are required for membrane formation in autophagy. The dynamic assembly of Atg proteins into the pre-autophagosomal structure dictates the localization and activity of the autophagic machinery.

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.

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.

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.

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.

Emerging evidence implicates autophagy in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. The authors of this Review discuss the control of cellular autophagy by nutrients, the regulation of energy metabolism by autophagy and the consequences of autophagy dysfunction and modulation in metabolic disease.

Autophagy is a beneficial adaptive response to cellular stress, but it can also benefit cancer cells, and can contribute to development of resistance to cancer treatments. The authors describe the complex roles of autophagy and the developments towards modulation of autophagy to improve the effectiveness of prostate cancer therapies.

Increasing evidence suggests that autophagy can modulate tissue responses during acute kidney injury, regulate podocyte homeostasis and protect against age-related renal disease. In this Review the authors describe the process of macroautophagy and its role in kidney health, ageing and disease. They also highlight the potential of autophagy as a target for renoprotective therapies.

Dysfunction of autophagy — an intracellular degradation pathway for cytosolic material — has been implicated in the pathogenesis of various neurodegenerative diseases. Rubinsztein and colleagues review recent progress in this area, focusing on macroautophagy, and discuss how this process may be manipulated to protect against neurodegeneration.

Autophagy serves to degrade proteins during starvation. Recent progress has illuminated how, during starvation and nutrient repletion, autophagy can mobilize diverse cellular energy and nutrient stores, such as lipids, carbohydrates and iron, to salvage key metabolites that sustain and facilitate core anabolic functions.

Autophagy underlies the cellular pathology of several rheumatic diseases. Targeting the signalling pathways involved has shown promise in recent clinical trials. Rockel and Kapoor discuss the key regulators involved in autophagy and therapeutic strategies currently in use and under development.

This article provides a comprehensive overview of the general functions of autophagy in immunity, the interactions between autophagy and immune signalling pathways and the role of autophagy–immune crosstalk in multicellular immune responses and disease.

A growing research community studies autophagy—a process of cellular recycling and maintenance—but there are some hot-button methodological issues.

One of two papers showing that loss of autophagy in the central nervous system of mice causes the accumulation of protein aggregates in inclusion bodies, neurodegeneration and premature death of the mice. This demonstrates that continuous clearance of cellular components is essential for proper housekeeping and vital to keep the neurons in tiptop shape.

One of two papers showing that loss of autophagy in the central nervous system of mice causes the accumulation of protein aggregates in inclusion bodies, neurodegeneration and premature death of the mice. This demonstrates that continuous clearance of cellular components is essential for proper housekeeping and vital to keep the neurons in tiptop shape.

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 initiates with the assembly of a preautophagosomal structure (PAS), triggered by the yeast Atg1 complex. Ohsumi, Noda and colleagues present the crystal structures of Atg13–Atg1 and Atg13–Atg17, revealing how starvation-induced dephosphorylation of Atg13 triggers formationof the Atg1 complex and PAS assembly.

The core mechanisms of autophagy are generally assumed to be broadly conserved between yeast and mammals. Cheng et al. show that the distribution of PtdIns(3)P between cytoplasmic and luminal leaflets of autophagosomes differs dramatically in yeast and mammalian cells, suggestive of different underlying mechanisms.

In yeast, the novel protein Atg40 is enriched in the cortical and cytoplasmic endoplasmic reticulum (ER), and loads these ER subdomains into autophagosomes to facilitate ER autophagy; Atg39 localizes to the perinuclear ER and induces autophagic sequestration of part of the nucleus, thus ensuring cell survival under nitrogen-deprived conditions.

A small-molecule inhibitor of the type III phosphatidylinositol 3-kinase, Vps34, binds the ATP binding pocket and prevents vesicle trafficking and autophagy.

Inclusions containing TDP43 are linked to pathologies in several neurodegenerative diseases such as ALS and FTD. Pathogenic TDP43 mutations are now found to shorten the protein's half-life in individual neurons. Stimulating autophagy with inhibitors improves TDP43 clearance and localization.