Mammalian ATG9s drive the autophagosome formation by binding to LC3

The autophagosome is a membranous organelle that executes macroautophagy (call autophagy hereafter for the sake of brevity). Although the biogenesis of autophagosome depends on continuous acquirement of necessary membrane components to support its growth, the underlying mechanism has remained uncertain. Herein, we report that the mammalian ATG9 family members (maATG9s) play master roles in this process. We show that maATG9s directly localize to the growing autophagosomal membrane through their Ubiquitin-interacting motives (UIMs), which interact with the UIM docking site (UDS) on LC3, a component of the autophagosomal membrane. Interrupting the UIM-UDS interaction abrogates the maATG9s-LC3 binding, the localization of maATG9s to the growing autophagosome, and the autophagosome formation. Collectively, our findings show the first evidence that maATG9s act as primary autophagosomal membrane components to drive the autophagosome formation. As autophagy has been implicated in many human diseases, the identified maATG9s-LC3 interaction may serve as a target for manipulating pathological autophagosome formation.