Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins

Cadwell, Ken; Debnath, Jayanta

Autophagy consists of three cellular self-eating mechanisms that converge on the lysosome: microautophagy, chaperonemediated autophagy, and macroautophagy. Among these, macroautophagy (hereafter called autophagy) is the most well studied and genetically controlled by ATGs. Classic autophagy proceeds through multiple "canonical" steps that include (1) initiation by an autophagy-inducing signal, (2) nucleation of an isolation membrane or phagophore assembly site, (3) elongation and sealing of this double membrane around the cargo to be sequestered to form an autophagosome, (4) docking and fusion of the autophagosome with the lysosome to form an autolysosome, and (5) degradation of the vesicle contents by lysosomal enzymes ( Fig. 1 A) . Initiation, nucleation, and elongation require the hierarchical recruitment and activity of ∼15 ATGs and other proteins to the phagophore assembly site to construct the autophagosome (Codogno et al., 2011; Mizushima et al., 2011) . In this context, the term "noncanonical autophagy" refers to the formation of classic double membrane autophagosomes that does not require the activity of one or more key ATGs. Nonetheless, both canonical and noncanonical autophagy are fundamentally autodigestive pathways requiring autophagosome formation, followed by fusion with the lysosome (Codogno et al., 2011). Adding to this complexity, ATG proteins, both individually and as part of larger networks, control pathways that either do not involve the formation of a classic autophagosome or do not terminate in lysosomal degradation and nutrient recycling (Subramani and Malhotra, 2013) . Although not inclusive, the list of autophagy-related processes includes secretion and exocytosis, LC3-associated phagocytosis (LAP), viral replication