In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-XL and Mcl-1 but in the absence of active BH3-only proteins

• Published in: Cell death & disease Vol. 6; no. 11; p. e1996
• Main Authors: Senft, D, Weber, A, Saathoff, F, Berking, C, Heppt, M V, Kammerbauer, C, Rothenfusser, S, Kellner, S, Kurgyis, Z, Besch, R, Häcker, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-11-2015; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/2; 631/80/82/23; 631/80/86; Animals; Antibodies; Apoptosis - physiology; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-X Protein - deficiency; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Survival - physiology; Cells, Cultured; Endothelial Cells - ultrastructure; Fibroblasts; Humans; Immunology; Keratinocytes; Life Sciences; Mice; Mitochondria - metabolism; Myeloid Cell Leukemia Sequence 1 Protein - deficiency; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Original; original-article; Proto-Oncogene Proteins c-bcl-2 - deficiency; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transfection
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.341

Mitochondrial apoptosis is controlled by proteins of the B-cell lymphoma 2 (Bcl-2) family. Pro-apoptotic members of this family, known as BH3-only proteins, initiate activation of the effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), which is counteracted by anti-apoptotic family members. How the interactions of Bcl-2 proteins regulate cell death is still not entirely clear. Here, we show that in the absence of extrinsic apoptotic stimuli Bak activates without detectable contribution from BH3-only proteins, and cell survival depends on anti-apoptotic Bcl-2 molecules. All anti-apoptotic Bcl-2 proteins were targeted via RNA interference alone or in combinations of two in primary human fibroblasts. Simultaneous targeting of B-cell lymphoma-extra large and myeloid cell leukemia sequence 1 led to apoptosis in several cell types. Apoptosis depended on Bak whereas Bax was dispensable. Activator BH3-only proteins were not required for apoptosis induction as apoptosis was unaltered in the absence of all BH3-only proteins known to activate Bax or Bak directly, Bcl-2-interacting mediator of cell death, BH3-interacting domain death agonist and p53-upregulated modulator of apoptosis. These findings argue for auto-activation of Bak in the absence of anti-apoptotic Bcl-2 proteins and provide evidence of profound differences in the activation of Bax and Bak.