Autophagosomes

Autophagosomes are double-membrane vesicles that sequester cytoplasmic material and deliver it to lysosomes for degradation, forming a central vesicle in macroautophagy. They play a key role in cellular quality control and energy homeostasis by removing damaged organelles, protein aggregates, and other cytoplasmic components.

They originate from membrane precursors that expand into phagophores and close to form autophagosomes. The membrane sources include the endoplasmic reticulum (ER) and related compartments, with Atg9-containing vesicles contributing membrane and lipids from mitochondria-associated membranes. This process is highly coordinated with autophagy-related (Atg) proteins.

Formation involves initiation by the ULK1 complex (ULK1/2, ATG13, FIP200, ATG101) regulated by nutrient signals; inhibition of mTORC1 activates ULK1. The Beclin-1–VPS34 class III PI3K complex generates PI3P, nucleating the isolation membrane. Expansion requires Atg conjugation systems: ATG12–ATG5–ATG16L1 drives lipidation of LC3, and LC3 is conjugated to phosphatidylethanolamine to form LC3-II, which associates with autophagosomal membranes and serves as a common marker of autophagosomes.

Closure forms a mature autophagosome, which then undergoes maturation by docking and fusion with lysosomes. This fusion is mediated by Rab7 and SNAREs such as syntaxin 17, VAMP8, SNAP29, and the HOPS tethering complex, yielding an autolysosome where cargo is degraded by lysosomal enzymes.

Autophagosomes can sequester material nonselectively during nutrient deprivation or selectively via cargo receptors (p62/SQSTM1, NBR1, NDP52, OPTN) that bind ubiquitinated cargo and LC3 family proteins, directing specific cargo to autophagosomes for degradation.

Autophagosomes are thus central to cellular homeostasis, responses to stress, and defense against pathogens. Dysregulation is associated with neurodegenerative diseases, infections, and cancer.