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

Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death). The Bcl-2 family of proteins are well-characterized regulators of apoptosis, 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 converge. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis, 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.

[1]  John Calvin Reed,et al.  Conversion of Bcl-2 from Protector to Killer by Interaction with Nuclear Orphan Receptor Nur77/TR3 , 2004, Cell.

[2]  W. Zong,et al.  BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. , 2001, Genes & development.

[3]  W. Bursch.  The autophagosomal–lysosomal compartment in programmed cell death , 2001, Cell Death and Differentiation.

[4]  P. Clarke,et al.  Developmental cell death: morphological diversity and multiple mechanisms , 2004, Anatomy and Embryology.

[5]  Y. Ohsumi,et al.  Beclin–phosphatidylinositol 3‐kinase complex functions at the trans‐Golgi network , 2001, EMBO reports.

[6]  S. Korsmeyer,et al.  The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. , 2000, Molecular cell.

[7]  Toshiaki Mito,et al.  BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development. , 2003, Developmental cell.

[8]  Y. Tsujimoto.  Cell death regulation by the Bcl‐2 protein family in the mitochondria , 2003 .

[9]  James E. Goldman,et al.  Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel Bcl-2-Interacting Protein , 1998, Journal of Virology.

[10]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[11]  H. Hibshoosh,et al.  Induction of autophagy and inhibition of tumorigenesis by beclin 1 , 1999, Nature.

[12]  Eric H. Baehrecke,et al.  How death shapes life during development , 2002, Nature Reviews Molecular Cell Biology.

[13]  J. Flannery,et al.  bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[14]  E. Cheng,et al.  Conversion of Bcl-2 to a Bax-like death effector by caspases. , 1997, Science.

[15]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[16]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death , 2001, Science.

[17]  Y. Tsujimoto,et al.  Bcl-2 expression prevents activation of the ICE protease cascade. , 1996, Oncogene.

[18]  Takeshi Tokuhisa,et al.  Dissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem Cells , 2001, The Journal of cell biology.