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

• DOI: 10.1016/j.molcel.2011.10.014
• Publication Date: 2011-12-11T04:31:07Z
• Authors: Assaf D. Rubinstein; Miriam Eisenstein; Yaara Ber; Shani Bialik; Adi Kimchi
• Keywords: HEK293 Cells; Proto-Oncogene Proteins c-bcl-2; Autophagy; Small Ubiquitin-Related Modifier Proteins; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Apoptosis; Cell Biology; Molecular Biology; Autophagy-Related Protein 12; Mitochondria

Autophagy 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.