Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1.
The anti-apoptotic proteins Bcl-2 and Bcl-X(L) bind and inhibit Beclin-1, an essential mediator of autophagy. Here, we demonstrate that this interaction involves a BH3 domain within Beclin-1 (residues 114-123). The physical interaction between Beclin-1 and Bcl-X(L) is lost when the BH3 domain of Beclin-1 or the BH3 receptor domain of Bcl-X(L) is mutated. Mutation of the BH3 domain of Beclin-1 or of the BH3 receptor domain of Bcl-X(L) abolishes the Bcl-X(L)-mediated inhibition of autophagy triggered by Beclin-1. The pharmacological BH3 mimetic ABT737 competitively inhibits the interaction between Beclin-1 and Bcl-2/Bcl-X(L), antagonizes autophagy inhibition by Bcl-2/Bcl-X(L) and hence stimulates autophagy. Knockout or knockdown of the BH3-only protein Bad reduces starvation-induced autophagy, whereas Bad overexpression induces autophagy in human cells. Gain-of-function mutation of the sole BH3-only protein from Caenorhabditis elegans, EGL-1, induces autophagy, while deletion of EGL-1 compromises starvation-induced autophagy. These results reveal a novel autophagy-stimulatory function of BH3-only proteins beyond their established role as apoptosis inducers. BH3-only proteins and pharmacological BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin-1 and Bcl-2 or Bcl-X(L).
Maiuri
M Chiara
MC
INSERM U848, Villejuif, France.
Le Toumelin
Gaëtane
G
Criollo
Alfredo
A
Rain
Jean-Christophe
JC
Gautier
Fabien
F
Juin
Philippe
P
Tasdemir
Ezgi
E
Pierron
Gérard
G
Troulinaki
Kostoula
K
Tavernarakis
Nektarios
N
Hickman
John A
JA
Geneste
Olivier
O
Kroemer
Guido
G
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy; D000071186:Beclin-1; D015153:Blotting, Western; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D034622:RNA Interference; D020798:Two-Hybrid System Techniques; D051020:bcl-X Protein / Q000378:metabolism* / Q000648:ultrastructure
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D051020:bcl-X Protein