long-lived or aggregated proteins within double-membrane structures, followed by delivery of the cargo to lysosomes for degradation. Autophagy can also be induced by pathogen-recognition receptors such as TLR or NOD or other immune system-related signals. The breakthrough discovery of autophagy-related genes (ATG) in yeast and the subsequent identification of orthologs in higher organisms have paved the way for elucidating the major steps of the pathway. The core components and main steps of the pathway have been identified, yet many molecular details and underlying mechanisms remain to be determined. Initiation of autophagy or formation of a phagophore, its nucleation, elongation and closure to form the autophagosome and the maturation of the autophagosome to an autolysosome engages several protein complexes. Among the core subsets, the Ulk/Atg13/Atg17 protein kinase complex is involved in the initiation step. The mTOR pathway via mTORC1 complex negatively regulates Ulk; inactivation of mTOR leads to subsequent  phosphorylation events. Ulk kinases and Rb1cc1 are the orthologs of yeast Atg1 and Atg17, respectively. Nucleation of the phagophore membrane involves the class III PI3-kinase complex. In addition to the catalytic and regulatory subunits,  it contains Atg14 and Becn1, the ortholog of yeast Atg6. It is not well understood how these two complexes communicate. Becn1 also serves as a platform for the interaction with several proteins to play distinct roles in later phases. Elongation and closure of the phagophore are mediated by two ubiquitin-like conjugation systems, Atg12 and LC3 (Atg8 orthologs), respectively. The nucleation complex and other proteins mediate the recruitment of the first system which in turn, plays a role in recruiting the second. Atg12 is conjugated to Atg5 in an Atg7- (E1-like) and Atg10- (E2-like) dependent manner and is stabilized by Atg16. LC3 is primed by Atg4 and is conjugated to PE in an Atg7-, Atg3- (E2-like) and  Atg12-Atg5-Atg16 complex-dependent manner. Maturation of the autophagosome and its fusion with a lysosome to form the autolysosome, or prior to it with an endosome to form an amphisome (not shown),  is under the control of several proteins that include members of the Rab family, of ESCRT and SNARE complexes, and Becn1. A Becn1 complex with Uvrag and Rubicon downregulates these events while one without Rubicon upregulates them. Another subset of autophagy proteins is represented by transmembrane proteins, two in mammals and one, Atg9, in yeast. Their putative function is to carry lipids or deliver membrane. Within the autolysosome, the sequestered material is degraded by lysosomal enzymes such as Acp2 with Lamp proteins also being involved in the degradation process; derived metabolites may be effluxed for reuse. Cross-talk between autophagy and apoptosis has been evidenced and involves Becn1 and Bcl proteins. Deregulation of autophagy has been linked to cancer, neurodegeneration, cardiovascular and infectious diseases. To see the ontology report for annotations, GViewer and download, click here
[click to see the ontology report for related GO term - GO:0006914 and KEGG map - map04140]...(less)