The cellular events during autophagy follow distinct stages: vesicle nucleation (formation of the isolation membrane/phagophore), vesicle elongation and completion (growth and closure), fusion of the double-membraned autophagosome with the lysosome to form an autolysosome, and lysis of the autophagosome inner membrane and breakdown of its contents inside the autolysosome. This process occurs at a basal level and is regulated by numerous different signaling pathways (see text for references). Shown here are only the regulatory pathways that have been targeted pharmacologically for experimental or clinical purposes. Inhibitors and activators of autophagy are shown in red and green, respectively. At the molecular level, Atg proteins form different complexes that function in distinct stages of autophagy. Shown here are the complexes that have been identified in mammalian cells, with the exception of Atg13 and Atg17 that have only been identified in yeast. The autophagy pathway has numerous proposed physiological functions; shown here are functions revealed by in vivo studies of mice that cannot undergo autophagy (see Table 1).

Normal proteins are routinely turned over by different protein degradation systems, including the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy (referred to herein as “autophagy”). In autophagy-deficient neurons, there is an accumulation of ubiquitinated protein aggregates that is associated with neurodegeneration. Similar effects of autophagy deficiency are observed in other postmitotic cells (hepatocytes, cardiomyocytes) under basal conditions. Proteins altered by mutations (such as polyglutamine expansion tracts), posttranslational modifications, or stress (such as oxidative stress, UV irradiation, toxins) undergo a conformational change, are recognized by molecular chaperones, and are either refolded and repaired or delivered to protein degradation systems (usually UPS or CMA). If these protein degradation systems are impaired or if the altered proteins form oligomeric complexes that cannot be recognized by the UPS or CMA, autophagy may be the primary route for the removal of these abnormal and potentially toxic proteins. Impaired autophagy is associated with the formation of protein aggregates and increased neurodegeneration. The mechanisms by which abnormal proteins and impaired autophagy result in neurodegeneration are not known.

An increased on-rate of autophagy occurs in response to stress signals, resulting in increased autophagosomal and autolysosomal accumulation and successful execution of the adaptive physiological functions of autophagy. In certain disease states or upon treatment with lysosomal inhibitors, there is a reduced off-rate resulting in impaired lysosomal degradation of autophagosomes. This results in increased autophagosomal accumulation and adverse pathophysiological consequences related to unsuccessful completion of the autophagy pathway. A decreased on-rate is observed if signaling activation of autophagy is defective or mutations are present in ATG genes. This results in decreased autophagosomal accumulation, the accumulation of protein aggregates and damaged organelles, and pathophysiological consequences related to deficient protein and organelle turnover. The physiological and pathophysiological consequences listed for “increased on-rate,” “reduced off-rate,” and “decreased on-rate” are based on knockout studies of the ATG genes in model organisms.

In xenophagy, intracellular pathogens (bacteria, protozoans, and viruses) that are either inside the cytosol or in pathogen-containing vacuoles are surrounded by isolation membranes, engulfed into autophagosomes, and degraded inside autolysosomes. Autophagy may be involved in the activation of innate immunity by delivering viral nucleic acids to endosomal compartments containing Toll-like receptor 7 (TLR7), which signals the induction of type 1 interferon (IFN) production. Autophagy may be involved in adaptive immunity by delivering endogenously synthesized microbial antigens and self-antigens to late endosomes, where they are loaded onto MHC class II molecules for presentation to CD4⁺ T cells.