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

Cadwell, Ken; Debnath, Jayanta

Overall, these studies illustrate the wide array of nonautophagic functions mediated by the ATG machinery. These diverse functions deepen our understanding of ATGs in enacting cellautonomous and non-cell-autonomous biological functions beyond self-eating in both normal and disease states. They also broach the importance of revisiting phenotypes and functions, both in vitro and in vivo, that to date have been attributed to classic autophagy based on the genetic analysis of a single individual ATG. Going forward, it will be critical for future researchers to keep in mind alternative pathways, not just autophagy, upon discovering new ATG-dependent phenotypes. Importantly, in future studies to delineate how autophagy influences both normal physiology and disease, it will be incumbent on researchers to interrogate multiple ATGs controlling distinct elements of the autophagy trafficking pathway to definitively attribute a role for classic autophagy on cell fate and function. In a similar vein, as we develop more precise methods to therapeutically target specific autophagy machinery components, the role of alternative autophagy-related processes and signaling pathways merit thoughtful and rigorous consideration.