BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program

• Published in: Science (American Association for the Advancement of Science) 2010-12, Vol.330 (6009), p.1390-1393
• Main Authors: Ren, Decheng, Tu, Ho-Chou, Kim, Hyungjin, Wang, Gary X, Bean, Gregory R, Takeuchi, Osamu, Jeffers, John R, Zambetti, Gerard P, Hsieh, James J.-D, Cheng, Emily H.-Y
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Animals; Apoptosis; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; bcl-2 Homologous Antagonist-Killer Protein - chemistry; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-2-Associated X Protein - chemistry; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Bcl-2-Like Protein 11; BH3 Interacting Domain Death Agonist Protein - deficiency; BH3 Interacting Domain Death Agonist Protein - genetics; BH3 Interacting Domain Death Agonist Protein - metabolism; Biological and medical sciences; Caspases - metabolism; Cell death; Cell physiology; Cells, Cultured; Cerebellum - cytology; Cytochromes; Cytochromes c - metabolism; Cytokines; Fundamental and applied biological sciences. Psychology; Intracellular Membranes - metabolism; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Models, Biological; Molecular and cellular biology; Neurons; Neurons - physiology; Permeability; Potassium; Protein Multimerization; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Stress, Physiological; T lymphocytes; T-Lymphocytes - physiology; Thymocytes; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1190217

Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c-mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.