BH3 mimetics reveal the network properties of autophagy-regulatory signaling cascades

Beclin 1 usually interacts with several autophagy-inhibitory proteins including the anti-apoptotic proteins from the Bcl-2 family (Bcl-2, Bcl-X _Land Mcl-1) and the inositol-1,4,5 trisphosphate (IP₃) receptor, which interacts with Beclin 1 indirectly via Bcl-2. Beclin 1 possesses a BH3 domain that usually interacts with a hydrophobic cleft, the BH3 receptor domain, contained within Bcl-2 and its homologues. Dissociation of this interaction can be induced by phosphorylation or ubiquitination of the BH3 domain, by post-transcriptional modifications affecting the Bcl-2 protein, as well as by other BH3 domain-containing proteins that have a high affinity for Bcl-2 (or its homologues), and hence liberate Beclin 1 from its restraint. As a result, it has been thought that so-called BH3 mimetics, that is the pharmacological agents that occupy the hydrophobic cleft of Bcl-2, Bcl-X _L and Mcl-1, would induce autophagy solely by disrupting the interaction between Beclin 1 and its inhibitors. Unexpectedly, we found that two distinct BH3 mimetics, ABT737 and HA14-1, also stimulate other proautophagic pathways and hence activate the nutrient sensors Sirtuin 1 and AMPK, inhibit mTOR, deplete cytoplasmic p53 and trigger the IKK kinase. All these additional activities are required for optimal autophagy induction by BH3 mimetics, pointing to the existence of a coordinated autophagy-regulatory network.