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

Nat Cell Biol. 2004 Dec;6(12):1221-8. doi: 10.1038/ncb1192. Epub 2004 Nov 21.

Abstract

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-x(L)), and was also modulated by Bcl-x(L). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Animals
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins
  • Autophagy / genetics*
  • Autophagy-Related Protein 5
  • Beclin-1
  • Cells, Cultured
  • Etoposide / pharmacology
  • Fibroblasts / metabolism*
  • Fibroblasts / ultrastructure
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA Interference
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Ubiquitin-Protein Ligases
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein

Substances

  • ATG5 protein, S cerevisiae
  • Apoptosis Regulatory Proteins
  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • BAK1 protein, human
  • BAX protein, human
  • BCL2L1 protein, human
  • Bak1 protein, mouse
  • Bax protein, mouse
  • Bcl2l1 protein, mouse
  • Beclin-1
  • Becn1 protein, mouse
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Saccharomyces cerevisiae Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • 3-methyladenine
  • Etoposide
  • Ubiquitin-Protein Ligases
  • Adenine