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

Cadwell, Ken; Debnath, Jayanta

In addition to its established role in lysosomal degradation, the autophagy machinery controls extracellular secretion. Evidence to date most notably implicates ATGs in unconventional secretion of proteins lacking an N-terminal signal sequence (Dupont et al., 2011; Deretic et al., 2012; Malhotra, 2013; Subramani and Malhotra, 2013) . Whereas the majority of eukaryotic secretory proteins classically transit to the surface via the ER and Golgi apparatus, a growing list of proteins traffic through unconventional mechanisms that do not require insertion into the ER and/or bypass the Golgi (Rabouille et al., 2012; Malhotra, 2013) . In addition, some classically secreted proteins appear to be preferentially rerouted through unconventional pathways to facilitate trafficking during stress (Gee et al., 2011) . Studies to date have uncovered clear genetic requirements for two proteins originally implicated in the stacking of the Golgi apparatus, GRA SP55 and GRA SP65, as well as ATGs in mediating these alternative secretory pathways (Rabouille et al., 2012; Malhotra, 2013; Zhang and Schekman, 2013) . ATGs have been genetically linked to the unconventional secretion of acyl-CoA-binding protein Acb1 in yeast (AcbA in Dictyostelium discoideum; Duran et al., 2010; Manjithaya et al., 2010) , several inflammatory mediators in mammalian cells, including IL-1β and IL-18; the high mobility group protein B1 (HMGB1); and finally, the plasma membrane trafficking of the integral membrane protein ΔF508 CFTR (Dupont et al., 2011; Figure 1 . Classic autophagy compared with related trafficking pathways. (A) Classic autophagy: Diverse stimuli elicit the hierarchical recruitment and activity of multiple ATGs (yellow) and other regulatory proteins (blue) to construct the double membrane autophagosome. The lipidation of LC3 (LC3-II) is crucial for the capture of autophagic cargo and to stabilize of the inner autophagosomal membrane. The autophagosome subsequently fuses with the lysosome in a STX17-dependent manner, resulting in degradation of the vesicle contents by lysosomal enzymes. (B) Secretory autophagy: ATGs mediate the unconventional secretion of multiple proteins (e.g., Acb1 in yeast, and IL-1β, IL-18, and HMGB1 in mammalian cells) that lack an N-terminal signal sequence. These targets are postulated to be released via several putative mechanisms. First, the ATG conjugation machinery promotes the formation of an LC3 + autophagosome-like intermediate, and the contents enwrapped within the inner membrane of autophagosome are released extracellularly instead of degraded in lysosomes. Second, targets of secretory autophagy, such as IL-1β, are translocated into the intramembrane space of an LC3 + double membrane vesicular intermediate that fuses directly with the plasma membrane or fuses with a MVB intermediate that is secreted. Last, although formal experimental evidence is lacking, secretory autophagy may involve an MVB/amphisome intermediate and the exocytic release of small extracellular microvesicles. Regardless of the exact pathway, recent work indicates that secretory autophagy proceeds through a dedicated SNA RE machinery, which diverts secreted targets away from the lysosome and toward the plasma membrane (PM). (C) LAP: the phagocytosis of pathogens and other prey in certain cell types (e.g., macrophages and dendritic cells) recruits UVR AG and Rubicon (RUB CN), thereby activating the Beclin-1-VPS34 complex to generate phosphatidylinositol 3-phosphate and