A Complex between Atg7 and Caspase-9 A NOVEL MECHANISM OF CROSS-REGULATION BETWEEN AUTOPHAGY AND APOPTOSIS

Background: Several cross-talk mechanisms between autophagy and apoptosis have been identified, where the same protein plays a central role in the opposing processes. Results: This study identified a novel cross-talk mechanism involving an Atg7caspase-9 complex. Conclusion: Atg7 and caspase-9 mutually regulate each other's activity. Significance: The Atg7caspase-9 complex may determine the balance between autophagy and apoptosis in response to stress. Several cross-talk mechanisms between autophagy and apoptosis have been identified, in which certain co-regulators are shared, allowing the same protein to participate in these opposing processes. Our studies suggest that caspase-9 is a novel co-regulator of apoptosis and autophagy and that its caspase catalytic activity is dispensable for its autophagic role. We provide evidence that caspase-9 facilitates the early events leading to autophagosome formation; that it forms a complex with Atg7; that Atg7 is not a direct substrate for caspase-9 proteolytic activity; and that, depending on the cellular context, Atg7 represses the apoptotic capability of caspase-9, whereas the latter enhances the Atg7-mediated formation of light chain 3-II. The repression of caspase-9 apoptotic activity is mediated by its direct interaction with Atg7, and it is not related to the autophagic function of Atg7. We propose that the Atg7caspase-9 complex performs a dual function of linking caspase-9 to the autophagic process while keeping in check its apoptotic activity.