Autophagy is a catabolic process that envelopes, degrades, and recycles cytoplasmic material especially during times of stress. It is widely believed that the pro-survival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) block autophagy by binding to the BH3-like domain of Beclin 1. However, because Bcl-2, Bcl-xL, and Mcl-1 also inhibit the pro-apoptotic activity of Bax and Bak, and many inducers of autophagy also cause cell death, we wondered whether the current model might be spurious. To distinguish whether Bcl-2, Bcl-xL, or Mcl-1 influence autophagy directly, or indirectly, through their effects on apoptosis, we compared normal cells to those lacking Bax and Bak. In cells with Bax and Bak, inhibiting the pro-survival Bcl-2 family members induced both autophagy and cell death, but when cells were unable to undergo mitochondria-mediated apoptosis, neither inhibiting nor over-expressing Bcl-2, Bcl-xL or Mcl-1 caused any detectable effect on LC3B lipidation, LC3B turnover, or autophagosome formation (1).

These results challenge the notion that Bcl-2, Bcl-xL or Mcl-1 function by interacting with Beclin 1 to regulate autophagy, but instead show that they affect autophagy indirectly. Next, we investigated how activation of Bax and Bak stimulates autophagy. We found caspase activation was not required for autophagy induction, indicating it is triggered at an early stage of apoptosis. Furthermore, stimulation of autophagy appears to be specifically regulated since only particular cell death mechanisms increased LC3B lipidation. We are currently investigating how these early stages of cell suicide initiate autophagy. We hypothesize that stimulation of autophagy is a last minute escape mechanism to prevent cell suicide.