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

Cadwell, Ken; Debnath, Jayanta

The mechanistic underpinnings of secretory autophagy are only beginning to emerge, and numerous questions remain unaddressed. First, despite the genetic interconnections between ATGs and Grh1, the yeast GRA SP orthologue, in S. cerevisiae, recent work questions whether autophagy and Grh1 truly converge on a common secretory pathway (Cruz-Garcia et al., 2014) . Second, although ATGs that promote early autophagosome formation are genetically required for unconventional secretion, it is unclear whether secretory autophagy targets are actually captured into the autophagosomal lumen ( Fig. 1 B) . In fact, recent work demonstrates that IL-1β secretion requires ATGs but proceeds via translocation into the intermembrane space of the autophagosome (Zhang et al., 2015; Fig. 1 B) . Third, it remains unclear how secreted targets are transported to the cell surface. Because evidence supports that contents of multivesicular bodies (MVBs) can be directly exported to the cell surface, most notably the release of small extracellular microvesicles (exosomes), a role for the late endocytic pathway seems attractive (Colombo et al., 2014; Fig. 1 B) . At the same time, recent evidence demonstrates interconnections between autophagy and the retromer complex, a protein assembly implicated in plasma membrane exocytosis of diverse molecules from early endosomes (Steinberg et al., 2013) . During metabolic stress, the induction of autophagy elicits LC3 + autophagic compartments that bind and sequester a key inhibitor of retromer complex, the RabGAP protein TBC1D5; as a result, autophagy activates the retromer-driven translocation of proteins to the plasma membrane surface, most notably the glucose transporter GLUT1/ SLC2A1 (Roy et al., 2017) . Last, defining the mechanisms by which targets of secretory autophagy are diverted away from lysosomal degradation remains an important question for further study. Indeed, recent work indicates that secretory autophagy involves autophagosome-like vesicles that bypass STX17dependent fusion with lysosomes; rather, they use the SNA RE protein SEC22B in combination with plasma membrane syntaxins to complete cargo secretion (Kimura et al., 2017; Fig. 1 ).