Autophagy

In macroautophagy a cup-shaped membrane (the phagophore, from ER-associated sites) expands around a portion of cytoplasm and closes to form a double-membraned autophagosome. This requires the ULK1 kinase complex, a class III PI3K complex containing Beclin-1, and ubiquitin-like conjugation systems that attach LC3 (Atg8) to the membrane — LC3-II is the standard marker. The autophagosome fuses with a lysosome to form an autolysosome, whose hydrolases degrade the contents; amino acids, fatty acids and sugars are exported back to the cytosol for reuse. Microautophagy engulfs cytoplasm directly by invagination of the lysosomal membrane, and chaperone-mediated autophagy translocates individual proteins carrying a KFERQ motif across the lysosomal membrane via Hsc70 and LAMP-2A.

Autophagy is suppressed by mTORC1 when nutrients and growth factors are plentiful and activated by nutrient deprivation (mTORC1 inactivity), low energy (AMPK) and stress; the drug rapamycin induces it by inhibiting mTOR. Selective autophagy targets specific cargo: damaged mitochondria (mitophagy, via PINK1 and the ubiquitin ligase Parkin), protein aggregates, excess peroxisomes and ER, and intracellular bacteria (xenophagy).

Autophagy keeps cells alive during starvation (e.g. the neonate before feeding is established), performs organelle quality control in long-lived cells such as neurons and myocytes, contributes to innate immunity, and underlies the atrophy of cells deprived of nutrients or trophic signals. The 2016 Nobel Prize (Yoshinori Ohsumi) recognised discovery of its mechanisms.