A nonautophagic role of ATG5 in regulating cell growth by targeting c-Myc for proteasome-mediated degradation.

Autophagy is a conserved biological process that maintains cell homeostasis by targeting macromolecules for lysosome-mediated degradation. The levels of autophagy are relatively lower under normal conditions than under stress conditions (e.g., starvation), as autophagy is usually stimulated after multiple stresses. However, many autophagy-related regulators are still expressed under normal conditions. Although these regulators have been studied deeply in autophagy regulation, the nonautophagic roles of these regulators under normal conditions remain incompletely understood. Here, we found that autophagy-related 5 (ATG5), which is a key regulator of autophagy, regulates c-Myc protein degradation under normal conditions through the ubiquitin-proteasome pathway. We also found that ATG5 binds c-Myc and recruits the E3 ubiquitin-protein ligase FBW7 to promote c-Myc degradation. Moreover, ATG5-mediated degradation of c-Myc limits cell growth under normal conditions and is essential for embryonic stem cell differentiation. Therefore, this study reveals a nonautophagic role of ATG5 in regulating of c-Myc protein degradation.