Autophagy is an evolutionarily conserved catabolic process that is ubiquitous among eukaryotic cells. It involves the sequestration of cytoplasmic components for lysosomal degradation, and its role is to maintain the balance between the production of cell structures, their degradation and their turnover. There seems to be a connection between autophagy and apoptosis — the autophagy protein beclin-1 has been shown to interact with the anti-apoptotic protein BCL2 — although the significance of this interaction has remained unknown. Pattingre et al. now report in Cell that BCL2 also functions as an anti-autophagy protein.

Disruption of the beclin-1 orthologue in yeast prevents starvation-induced autophagy. Would the interaction between beclin-1 and BCL2 affect the autophagy process? Pattingre and colleagues showed that the beclin-1–BCL2 interaction contributed to inhibiting beclin-1-induced autophagy in yeast and mammalian cells, as well as in murine cardiac muscle.

Next, the authors examined the effects of BCL2 expression on the formation and activity of the complex through which beclin-1 functions in autophagy with class III phosphatidylinositol 3-kinase (PI3K). They found that complex formation was inhibited by BCL2, and that BCL2 decreased the activity of beclin-1-associated class III PI3K activity. In addition, they showed that cellular nutrient status regulated the interaction between beclin-1 and BCL2, suggesting that the dissociation of BCL2 from beclin-1 might be important in stimulating autophagy in response to starvation or other physiological stimuli.

Pattingre et al. noted that beclin-1 mutants that were unable to bind BCL2 induced higher levels of autophagy associated with the induction of autophagy-mediated cell death. The authors proposed a model in which the beclin-1–BCL2 complex functions as a rheostat to ensure that autophagy levels remain within a physiological range — the consequence for straying outside this range being autophagy-dependent cellular demise.

The BCL2 family of proteins are pivotal intermediates in cell-death signalling. The new findings of Pattingre and colleagues indicate that BCL2 has a dual role in cell death: in addition to its well-known anti-apoptotic properties, BCL2 also functions as a brake on autophagy-induced cell death. Because autophagy genes have different physiolgical roles, including differentiation, development, tumour suppression and promoting survival under stress conditions, these results might represent a novel mechanism by which BCL2 contributes to the modulation of these processes.