Aims: Autophagy envelops and recycles cytoplasmic material especially during times of stress. It was widely believed that the anti-apoptotic Bcl-2 family of proteins block autophagy by binding directly to Beclin 1. We recently challenged this long-standing model by showing that the anti-apoptotic Bcl-2 family regulate autophagy by inhibiting Bax and Bak, which both permeabilize the outer mitochondrial membrane to induce apoptosis [Lindqvist et al. (2014) PNAS; Reljic et al. (2016) Autophagy]. However, it remained unclear why a cell suicide pathway would activate autophagy, which is usually pro-survival process.

Methods: By over-expressing BH3-only proteins or using BH3 mimetic compounds, we were able to monitor autophagy induced during apoptosis in the most direct manor. We used both immunoblotting and fluorescence-based autophagy markers in cells where different apoptotic proteins were either chemical inhibited or genetically lost to determine what stage in the cell death pathway in which autophagy is induced.

Results: We have now determined how and why Bax and Bak stimulate autophagy. We demonstrate that the loss of mitochondrial function correlated with an increase in intracellular [AMP]/[ATP], rapid phosphorylation of the AMP-sensor AMPK, and activation of the autophagy protein ULK1. Bax/Bak-mediated autophagy degrades damaged mitochondria. Importantly, our data demonstrates that Bax/Bak-mediated autophagy helps caspases keep apoptosis an immunologically silent form of cell death by reducing the amount of secreted pro-inflammatory cytokine interferon-β.

Conclusions: Our results present a novel role for autophagy, an essential cytoplasmic recycling process, in regulating immune signalling from apoptotic cells. This new cross-talk between apoptosis and autophagy changes our understanding of how cells prepare themselves to die.