Abstract

In macroautophagy (hereafter autophagy), cells form autophagosomes, transient double-membrane–bound compartments that engulf portions of the cytoplasm for targeted degradation in the lysosome/vacuole to maintain cellular homeostasis under basal and stress conditions. The de novo formation of autophagosomes is driven by hierarchical assembly and function of a sophisticated autophagy protein machinery, which mediates the substantial underlying membrane rearrangements (1, 2). Precursor membranes are nucleated into a single-membrane structure, termed the isolation membrane (IM) or phagophore, which dramatically expands in a cup-shaped manner and encapsulates proximal cargo of diverse size and nature. The closure of the IM results in the formation of an outer and inner vesicle, giving rise to the characteristic double-membrane autophagosome. The outer autophagosomal membrane then fuses with the lysosomal/vacuolar membrane, releasing the inner vesicle and enclosed cargo for degradation. The origin of the membrane lipids and the underlying mechanisms that drive the rapid expansion of IMs are still poorly understood. The biogenesis of autophagosomes occurs in close association with specialized subdomains of the endoplasmic reticulum (ER), often in close proximity to ER contacts with other organelles (3⇓⇓–6). In mammals, the omegasome, a transient ER subdomain enriched for phosphatidylinsositol-3-phosphate (PI3P), closely enwraps the forming IM (7, 8). The IM in yeast is spatially linked to ER exit sites [(ERESs), ER subdomains … [↵][1]1Email: martin.graef{at}age.mpg.de. [1]: #xref-corresp-1-1

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