Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes

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Abstract
Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death)1,2. The Bcl-2 family of proteins are well-characterized regulators of apoptosis3, and the multidomain pro-apoptotic members of this family, such as Bax and Bak, act as a mitochondrial gateway where a variety of apoptotic signals converge4,5,6. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis4,5,6, we found that these cells still underwent a non-apoptotic death after death stimulation. Electron microscopic and biochemical studies revealed that double knockout cell death was associated with autophagosomes/autolysosomes. This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-xL), and was also modulated by Bcl-xL. These results indicate that the Bcl-2 family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes.