Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex

Autophagy (cellular self-eating) is essential for the health and survival of eukaryotic cells. Therapeutic autophagy induction is a major goal in the field. Rubicon inhibits autophagy and is a potential target for autophagy inducers. Rubicon is localized to its site of action in the cell by binding to the small GTPase Rab7. Here, we report a high-resolution structure of a large part of Rubicon, known as the Rubicon Homology (RH) domain. We show how the RH domain binds to Rab7 and show that the Rab7-binding residues of Rubicon are essential for Rubicon localization and autophagy inhibition. This provides a roadmap to block Rubicon localization and activity in order to upregulate autophagy.