A Non-Autophagic Role of ATG5 in the Negative Regulation of Cell Growth by Targeting c-Myc for Proteasome-Mediated Protein Degradation

Autophagy is a conserved biological process that maintains cell homeostasis mainly by targeting macromolecules or organelles for lysosome-mediated degradation. The levels of autophagy are relatively lower under normal conditions than under stress conditions (e.g., starvation or infection), as autophagy is usually stimulated under such stress conditions. However, many autophagy-related regulators are still expressed under normal conditions. Although these regulators have been studied in depth in the context of 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 protein degradation. Moreover, ATG5-mediated regulation of c-Myc limits cell growth under normal conditions and is essential for embryonic stem cell differentiation. Therefore, this study reveals a novel nonautophagic role of ATG5 in the regulation of c-Myc protein degradation.