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Article Addendum
BH3-Only Proteins and BH3 Mimetics Induce Autophagy by Competitively Disrupting the Interaction between Beclin 1 and Bcl-2/Bcl-XL
Maria Chiara Maiuri, Alfredo Criollo, Ezgi Tasdemir, José Miguel Vicencio, Nicolas Tajeddine, John A. Hickman, Olivier Geneste and Guido Kroemer
volume 3 | issue 4
July/August 2007Pages: 374 - 376
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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-XL) by virtue of its BH3 domain, an amphipathic α-helix that binds to the hydrophobic cleft of Bcl-2/Bcl-XL. 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-XL. This causes autophagy of mitochondria (mitophagy) but not of the endoplasmic reticulum (ER-phagy). Only ER-targeted (not mitochondrion-targeted) Bcl-2/Bcl-XL can inhibit autophagy induced by Beclin 1, and only Beclin 1-Bcl-2/Bcl-XL 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-XL 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-XL at the level of the endoplasmic reticulum.
Addendum to:
Functional and Physical Interaction Between Bcl-XL and a BH3-Like Domain in Beclin-1
M.C. Maiuri, G. Le Toumelin, A. Criollo, J.-C. Rain, F. Gautier, P. Juin, E. Tasdemir, G. Pierron, K. Troulinaki, N. Tavernarakis, J.A. Hickman, O. Geneste and G. Kroemer
EMBO J 2007; In press
Authors
Maria Chiara Maiuri
INSERM; U848; Institut Gustave Roussy; Université Paris-Sud; Villejuif, France; Università degli Studi di Napoli �rico II” Facoltà di Scienze Biotecnologiche; Napoli, Italy
Alfredo Criollo
Institut Gustave Roussy
Ezgi Tasdemir
Institut Gustave Roussy
José Miguel Vicencio
Institut Gustave Roussy
Nicolas Tajeddine
Institut Gustave Roussy
John A. Hickman
Institut de Recherche Servier
Olivier Geneste
Institut de Recherche Servier
Guido Kroemer
INSERM; U848; Institut Gustave Roussy; Université Paris-Sud; Villejuif, France
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.