BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L)

Autophagy. Jul-Aug 2007;3(4):374-6. doi: 10.4161/auto.4237. Epub 2007 Jul 4.

Abstract

Beclin 1 has recently been identified as novel BH3-only protein, meaning that it carries one Bcl-2-homology-3 (BH3) domain. As other BH3-only proteins, Beclin 1 interacts with anti-apoptotic multidomain proteins of the Bcl-2 family (in particular Bcl-2 and its homologue Bcl-X(L)) by virtue of its BH3 domain, an amphipathic alpha-helix that binds to the hydrophobic cleft of Bcl-2/Bcl-X(L). The BH3 domains of other BH3-only proteins such as Bad, as well as BH3-mimetic compounds such as ABT737, competitively disrupt the inhibitory interaction between Beclin 1 and Bcl-2/Bcl-X(L). This causes autophagy of mitochondria (mitophagy) but not of the endoplasmic reticulum (reticulophagy). Only ER-targeted (not mitochondrion-targeted) Bcl-2/Bcl-X(L) can inhibit autophagy induced by Beclin 1, and only Beclin 1-Bcl-2/Bcl-X(L) complexes present in the ER (but not those present on heavy membrane fractions enriched in mitochondria) are disrupted by ABT737. These findings suggest that the Beclin 1-Bcl-2/Bcl-X(L) complexes that normally inhibit autophagy are specifically located in the ER and point to an organelle-specific regulation of autophagy. Furthermore, these data suggest a spatial organization of autophagy and apoptosis control in which BH3-only proteins exert two independent functions. On the one hand, they can induce apoptosis, by (directly or indirectly) activating the mitochondrion-permeabilizing function of pro-apoptotic multidomain proteins from the Bcl-2 family. On the other hand, they can activate autophagy by liberating Beclin 1 from its inhibition by Bcl-2/Bcl-X(L) at the level of the endoplasmic reticulum.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / physiology*
  • BH3 Interacting Domain Death Agonist Protein / metabolism*
  • Beclin-1
  • Humans
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism
  • Models, Biological
  • Models, Chemical
  • bcl-2-Associated X Protein / metabolism*
  • bcl-X Protein / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • Beclin-1
  • Membrane Proteins
  • bcl-2-Associated X Protein
  • bcl-X Protein