![]() ![]() ![]() ![]() 8 In addition to the two conjugation systems, four more protein complexes make up the remainder of the molecular machinery required for autophagy ( Fig. This conjugation is not involved in starvation-induced autophagy but is important for regulation of mitochondrial homeostasis and cell death. Very recently, mammalian ATG12 was also shown to conjugate to ATG3. Atg10 acts as an E2 for the conjugation of Atg12 to Atg5 to form a high-molecular-weight complex with Atg16, which then in turn assists the E2 Atg3 in the conjugation of phosphatidylethanolamine (PE) to Atg8. 6, 7 Two ubiquitin (Ub)-like protein conjugation systems involving the two Ub-like modifiers Atg8 and Atg12 constitute part of the evolutionarily conserved autophagic machinery. 2, 6 So far, 34 AuTophaGy-related ( ATG) genes have been reported in yeast and 15 of these are “core” ATG genes commonly required for the different autophagy pathways. Yeast genetics has been vital for the elucidation of the molecular machinery involved in autophagy processes. Fusion of autophagosomes with late endosomes or lysosomes (maturation step) is then required for the formation of autolysomes where the substrates are degraded. Closure results in the formation of a double-membrane autophagosome. Aggregation of the substrate and/or cargo receptor is required for efficient sequestration. ![]() Selective autophagy depends on binding of substrates to the inner surface of the growing phagophore, and this can be achieved by cargo receptors that are associated both with the substrate and with lipidated ATG8 family proteins anchored to the phagophore. This complex then acts as an E3 ligase assisting the E2 ATG3 in the lipidation of ATG8 family proteins at the phagophore. First, conjugation of ATG12 to ATG5 results in the formation of an oligomeric complex between the ATG12-ATG5 conjugate and ATG16L. Additional ATG proteins are required for growth of the phagophore (elongation step), that depends on two Ub-like conjugation reactions. Autophagosome formation is initiated (nucleation step) by the ULK1 complex and the class III PtdIns 3-kinase complex located at the phagophore. Model for selective autophagy in mammalian cells. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. Mounting evidence suggests that autophagy is a more selective process than originally anticipated. ![]()
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