Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1

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Abstract
The anti‐apoptotic proteins Bcl‐2 and Bcl‐XL 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‐XL is lost when the BH3 domain of Beclin‐1 or the BH3 receptor domain of Bcl‐XL is mutated. Mutation of the BH3 domain of Beclin‐1 or of the BH3 receptor domain of Bcl‐XL abolishes the Bcl‐XL‐mediated inhibition of autophagy triggered by Beclin‐1. The pharmacological BH3 mimetic ABT737 competitively inhibits the interaction between Beclin‐1 and Bcl‐2/Bcl‐XL, antagonizes autophagy inhibition by Bcl‐2/Bcl‐XL 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‐XL.