The Autophagy Protein Atg12 Associates with Antiapoptotic Bcl-2 Family Members to Promote Mitochondrial Apoptosis

SummaryAutophagy and apoptosis constitute important determinants of cell fate and engage in a complex interplay in both physiological and pathological settings. The molecular basis of this crosstalk is poorly understood and relies, in part, on “dual-function” proteins that operate in both processes. Here, we identify the essential autophagy protein Atg12 as a positive mediator of mitochondrial apoptosis and show that Atg12 directly regulates the apoptotic pathway by binding and inactivating prosurvival Bcl-2 family members, including Bcl-2 and Mcl-1. The binding occurs independently of Atg5 or Atg3 and requires a unique BH3-like motif in Atg12, characterized by interaction studies and computational docking. In apoptotic cells, knockdown of Atg12 inhibited Bax activation and cytochrome c release, while ectopic expression of Atg12 antagonized the antiapoptotic activity of Mcl-1. The interaction between Atg12 and Bcl-2 family members may thus constitute an important point of convergence between autophagy and apoptosis in response to specific signals.

► Atg12 was identified as a positive mediator of apoptosis in an siRNA screen ► Atg12 binds antiapoptotic Bcl-2 proteins via a BH3-like motif ► Binding of Atg12 to Mcl-1 suppresses the antiapoptotic activity of Mcl-1 ► Computational docking predicts that Atg12 binds Mcl-1 via two adjacent loops