title: The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Assaf D
authors.initials: AD
authors.lastname: Rubinstein
authors.forename: Miriam
authors.initials: M
authors.lastname: Eisenstein
authors.forename: Yaara
authors.initials: Y
authors.lastname: Ber
authors.forename: Shani
authors.initials: S
authors.lastname: Bialik
authors.forename: Adi
authors.initials: A
authors.lastname: Kimchi
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D025841:Small Ubiquitin-Related Modifier Proteins