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Our understanding of the basic mechanisms of autophagy is growing, but many questions remain about the types of autophagy cells use, when they use them, and how they function in different contexts. We asked emerging and established leaders in the field to discuss the questions and areas that they are most excited about to deepen our understanding of autophagy.

This timeline article pays tribute to the late James Fred 'Paulo' Dice, whose vision of selective protein degradation in lysosomes led to the discovery of chaperone-mediated autophagy.

Autophagy contributes to lipid catabolism through direct mobilization and breakdown of cellular lipid stores. Two recent studies reveal the regulatory mechanisms activated by cells during starvation to ensure that the cellular compartments involved in autophagic lipid catabolism are ready to receive, process and use these lipids. The regulators represent attractive therapeutic targets to help fight lipid-excess-associated diseases.

The plasma membrane is identified as a source for the formation of autophagosomes, the double membrane vesicles that deliver intracellular components to lysosomes for their degradation.

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.

Dysfunctional or aggregated proteins in cells are degraded by autophagy. Wong et al.study aggregates of the protein synphilin-1 and show that ubiquitination alters their dynamic properties, which determines whether the aggregates are degraded via basal or inducible forms of autophagy.

Soluble cytosolic proteins can be degraded in lysosomes by chaperone-mediated autophagy, however, the current method to measure this process requires isolation of lysosomes. Now, a fluorescent reporter is described that can measure this type of autophagy in intact cells.

The primary cilium is a microtubule-based organelle that functions in sensory and signal transduction; here the authors show that the primary cilium is required for activation of starvation-induced autophagy and that basal autophagy negatively regulates ciliogenesis.

Chaperone-mediated autophagy (CMA) helps maintain protein quality during cellular stress. Here the authors show that CMA is also activated in response to DNA damage and regulates degradation of the cell cycle regulator Chk1—the first nuclear protein shown to be a substrate of CMA.

Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.

The presence of autophagic morphology in failing heart muscle cells has suggested that autophagy causes heart failure. Instead, it seems that the opposite is true: autophagy is critical for normal heart function (pages 619–624).

Juste, Kaushik and co-workers show that the circadian regulation of chaperone-mediated autophagy orchestrates the degradation of clock components and contributes to the circadian remodelling of the proteome.

This study shows that Parkinson's disease–associated mutant forms of leucine-rich repeat kinase 2 (LRRK2) impair chaperone-mediated autophagy in neurons, thereby reducing degradation of α-synuclein by this pathway and contributing to the accumulation of this protein observed in brain tissue from patients with Parkinson's disease.

Connexins localize to the plasma membrane, where they form gap junctions between cells. Cuervo and colleagues report that connexins associate with autophagosome precursor structures in the plasma membrane and inhibit autophagosome biogenesis. Nutrient deprivation relieves this inhibition and promotes autophagic degradation of connexin proteins.

Structure-based design of RARα antagonists leads to compounds that can selectively upregulate chaperone-mediated autophagy (CMA), yielding the first chemically tractable target for regulating CMA in cells.

A hallmark of Huntington's disease is the accumulation of polyglutamine-expanded huntingtin (htt) protein in striatal neurons. The removal of cytosolic mutant htt is known to be mediated by the macroautophagy-lysosomal system. Here the authors specifically identify the defective step of autophagy in Huntington's models, in which autophagosomes fail to recognize mutant htt as a cargo destined for degradation.

Zhang, Cuervo and colleagues find that Huntingtin (Htt), which is commonly mutated in Huntington disease, regulates selective autophagy. Htt enhances interactions between p62, LC3 and ubiquitylated cargo and derepresses ULK1 kinase activity.

Cuervo and colleagues find that perilipin proteins associated with lipid droplets are degraded by chaperone-mediated autophagy to facilitate recruitment of the lipolytic machinery to lipid droplets.

The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release.

Haematopoietic stem cells show progressive functional decline with age that can be reversed by stimulation of chaperone-mediated autophagy in old mice and aged humans.

Chaperone mediated autophagy (CMA) is selective but its activity in different tissue types has been unclear due to a lack of tools. Here, the authors generate transgenic mice expressing a CMA reporter that provides spatial and temporal in vivo data, uncovering differences in CMA in distinct tissues.

Defects in the cellular homeostatic process of autophagy have been observed in various neurodegenerative disorders. In this Review, Wong and Cuervo highlight the latest literature to discuss different types of autophagic dysfunction in neurodegenerative conditions and compare the interplay between autophagy and other cellular degradation processes.

In this Perspective, the mechanisms by which proteostasis is coordinated within and between cells is discussed with an emphasis on how these mechanisms are deregulated upon aging.

The selective degradation of cellular components via chaperone-mediated autophagy (CMA) functions to regulate a wide range of cellular processes, from metabolism to DNA repair and cellular reprogramming. Recent in vivo studies have enabled to dissect key roles of CMA in ageing and ageing-associated disorders such as cancer and neurodegeneration.