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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.

Age-related decline of chaperone-mediated autophagy blunts the regenerative capacity of muscle stem cells, partly due to impaired glycolytic shift required for normal stem cell expansion.

Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.

Khawaja et al. show sex-specific differences in neuronal-activity regulation by chaperone-mediated autophagy and that loss of chaperone-mediated autophagy leads to defective neuronal physiology and increased seizure susceptibility, linking chaperone-mediated autophagy to neuronal excitability.

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.

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.

New treatments are essential for methicillin-susceptible Staphylococcus aureus bacteremia, but progress is slow. In this phase III–IV trial, cloxacillin plus fosfomycin failed to show superiority over cloxacillin alone, underscoring the challenges to improving patient outcomes.

Scientific questions are universal but the scientific workforce remains skewed, with women and gender minorities still underrepresented. Initiatives such as the Women in Autophagy network promote the careers of these underrepresented groups with a range of free, year-round scientific, mentoring and networking activities for all scientists.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

Using single-cell imaging of a fluorescent chaperone-mediated autophagy (CMA) reporter and RNA sequencing data, the authors present a resource on basal CMA activity across organs, cell types and sexes in young and old mice, offering a comprehensive overview of changes in this proteostatic mechanism in the context of aging.

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.

Haematopoietic stem cells (HSCs) are metabolically quiescent, with balanced myeloid and lymphoid potential. Here the authors show that MAEA is required in HSCs for ubiquitination and downregulation of surface cytokine receptors via autophagy; MAEA loss leads to impaired HSC quiescence and a myeloproliferative disorder.

The genome of double-stranded DNA bacteriophages is delivered to host cells through the viral portal and tail structures. Here the authors describe structures of the bacteriophage T7 portal and the 1.5 MDa tail complex formed by the portal protein, adaptor protein and nozzle, providing insight into how the portal and tail machinery work during DNA packaging and ejection.

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.

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.

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).

Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.

Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits.

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.

Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.

The Epstein-Barr virus (EBV) is a dangerous human pathogen responsible for mononucleosis and several types of cancers. Here the authors describe a high-resolution atomic structure of the EBV portal, which serves as the entrance and exit pore for the viral genome and is a potential pharmacological target for the development of antivirals.

Crop wild relatives’ genetic diversity is usually not considered in conservation planning. Here, the authors introduce an approach to identify conservation areas based on evolutionary and threat processes, by developing proxies of genetic differentiation, and including taxa’s habitat preferences.

In January 2024, a Hevolution Alliance for Aging Biomarkers thinktank convened at Cold Spring Harbor to discuss the framework for creating an open and diverse data resource for developing reliable aging biomarkers. As the funding for this initiative has now been confirmed, we summarize recommendations and key milestones for its implementation.

The earliest steps in autophagy are thought to include the budding of Atg16L-containing vesicles from the plasma membrane and their homotypic fusion to form a phagophore. Morozova et al. reveal a role for the membrane curvature-inducing protein Annexin A2 in the formation and fusion of these vesicles.

Description of a novel function for autophagy in regulating lipid metabolism, called 'macrolipophagy', in which lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. A critical role of autophagy in regulating lipid metabolism is identified, and may provide a new approach to prevent lipid accumulation in disease.

Niemann-Pick type C1 disease is most commonly caused by the allele NPC1 I1061T, which is misfolded in the ER and rapidly degraded by the ubiquitin proteasome system. Here the authors show that the I1061T mutant is also degraded by ER-phagy.

Risk variants of APOL1 associated with human chronic kidney disease have been identified, but causality has been unclear. Transgenic expression in mice now shows that such alleles can indeed cause renal disease.

Chaperone-mediated autophagy selectively targets single cytoplasmic proteins for degradation. Macian and colleagues show that such autophagy is induced by engagement of the TCR to target negative regulators of T cell activation.

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.

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.

Lyden and colleagues use asymmetric flow field-flow fractionation to classify nanoparticles derived from cell lines and human samples, including previously uncharacterized large, Exo-L and small, Exo-S, exosome subsets.