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In this Review, Kotani and Nakatogawa discuss recent advances in our understanding of the molecular basis of autophagy induction and delineate how diverse mechanisms converge on core principles to ensure context-specific control of autophagy initiation.

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.

In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.

Fujioka et al. show that, under starvation, yeast Atg1 forms droplets that concentrate autophagy factors, boosting Atg8 lipidation and clustering vesicles. These droplets likely serve as hubs that generate membrane seeds for autophagosome formation.

Autophagy is a process in which cytoplasmic components are broken down to supply materials for the synthesis of essential molecules under nutrient-limiting conditions. Because this process involves random sequestration of the cytoplasm by large membrane vesicles, considerable amounts of molecules, such as ribosomes, are necessarily degraded by autophagy. However, starving cells also promote additional selective degradation of ribosomes as a requirement for survival.

Macronucleophagy degrades nuclear components. Here, the authors use yeast cells to show that macronucleophagy can act as a break to limit micronucleophagy, another mode of autophagic degradation of nuclear components, and that this may play a role in protection against starvation.

Here, the authors show that the complete set of the Atg8–E1–E2–E3 conjugation machinery forms an interaction web through multivalent weak interactions, which mediates membrane shaping observed during autophagosome formation.

How membrane morphology is regulated during autophagosome formation remains elusive. Here, authors reveal a mechanism by which the forming autophagosomal membrane expands with a large opening for non-selective sequestration of the cytoplasm.

The ER is subject to autophagy (ER-phagy) for turnover, with Atg40 acting as a receptor to sequester ER with Atg8 in autophagosomes. Here, the authors show that Atg40 is clustered by interaction with Atg8 to generate local membrane curvature and promote autophagosome packing.

Lipidated Atg8 affects membrane morphology via two aromatic membrane-facing residues that are important for autophagy in budding yeast and mammalian cells.

Cryo-EM and liposome assays reveal that Atg9 functions as a lipid scramblase, transporting phospholipids between inner and outer liposome leaflets. Analyses of mutants in yeast support a role for this activity in autophagy.

Structural and biochemical data suggest that the essential autophagy protein Atg2 acts as a lipid-transfer protein that supplies phospholipids from the source organelle (especially the ER) to the isolation membranes (IMs) for autophagosome formation.

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.

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.

It remains unclear why quiescent neural stem cells (qNSCs) in the subventricular zone of the mouse brain have enlarged lysosomes. Here, authors demonstrate that qNSCs exhibit higher lysosomal activity and degrade activated EGF receptor by endolysosomal degradation more rapidly than proliferating NSCs, which prevents the NSC exit from quiescence.

Autophagy involves engulfment of cellular components into double-membrane vesicles called autophagosomes. The biogenesis of autophagosomes requires the cooperation of multiple proteins and lipids from various membrane sources. Our understanding of the molecular mechanisms of the initiation, growth, bending and closure of autophagosomal membranes is expanding at a rapid pace.