Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak

It is widely accepted that prosurvival B-cell lymphoma 2 (Bcl-2) family members not only inhibit apoptosis but also negatively regulate autophagy by binding to Beclin 1. Herein, we challenge this view and provide genetic and biochemical evidence that the effects of prosurvival Bcl-2 family members on autophagy are instead an indirect consequence of their inhibition of apoptosis mediators Bcl-2–associated X (Bax) and Bcl-2 homologous antagonist/killer (Bak). We show that in the absence of Bax and Bak, antagonizing or altering the levels of prosurvival Bcl-2 family members has no detectable impact on autophagy. Because several inhibitors of both autophagy and Bcl-2 are in clinical trials for the treatment of cancer, it is important to understand the cross-talk between these pathways.