The TBC/RabGAP Armus regulates autophagy via a cross-talk between the small GTPases Rac1 and Rab7

• Main Author: Carroll, Bernadette
• Other Authors: Braga, Vania ; Magee, Tony
• Published: Imperial College London 2013
• Subjects: 616.07
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.693949

Autophagosomes are specialised, double membrane-bound organelles that participate in the bulk degradation of cytoplasmic proteins and organelles during autophagy. Autophagy is required for the maintenance of general cellular health and survival and is particularly important in stress conditions such as nutrient starvation. As critical participants in membrane trafficking events, Rab GTPases, along with their positive (GEF) and negative (GAP) regulators are indispensable for autophagy. Indeed, a number of RabGAP proteins have been implicated in the control of autophagy and increasingly it appears that their contribution exceeds that of just inactivating Rab GTPases. Armus is a TBC/RabGAP protein that specifically inactivates Rab7 and can also bind active Rac, a member of the Rho family of small GTPases. By mediating cross-talk between these two small GTPases, Armus participates in the regulation of E-cadherin degradation during cell scattering. I have identified that during nutrient starvation, Armus is required for efficient autophagy to occur in normal human keratinocytes. Furthermore, the activities of Rab7 and Rac are inversely correlated during starvation; Rab7 is transiently activated while Rac is potently inactivated. This inactivation is required but not sufficient to induce autophagosome formation and occurs independently of signaling via mTORC1. Rather, we hypothesise that Rac is out-competed for binding to Armus by the autophagosome-specific protein, LC3. Armus is able to directly interact with LC3 via two complementary, LC3-interacting region (LIR) motifs. This interaction is required for the recruitment of Armus to autophagosomes and away from cell-cell contacts, which remain unperturbed during nutrient starvation. The subsequent localisation of Armus at autophagosome membranes provides it with the appropriate spatial distribution to facilitate autophagosome maturation in a RabGAP-dependent manner. We have observed that autophagy occurs at disparate levels in epithelial tumour cell lines. Further understanding of the specific signaling and trafficking events that regulate autophagy will have important future implications in health and disease.