The TBC/RabGAP Armus Coordinates Rac1 and Rab7 Functions during Autophagy

• Published in: Developmental cell Vol. 25; no. 1; pp. 15 - 28
• Main Authors: Carroll, Bernadette, Mohd-Naim, Noor, Maximiano, Filipe, Frasa, Marieke A., McCormack, Jessica, Finelli, Mattea, Thoresen, Sigrid B., Perdios, Louis, Daigaku, Reiko, Francis, Richard E., Futter, Clare, Dikic, Ivan, Braga, Vania M.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-04-2013; Cell Press
• Subjects: Amino Acid Sequence; Autophagy; Culture Media - metabolism; Enzyme Activation; Fluorescent Antibody Technique; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanosine Triphosphate - genetics; Guanosine Triphosphate - metabolism; Humans; Infant, Newborn; Keratinocytes - metabolism; Keratinocytes - pathology; Lysosomes - genetics; Lysosomes - metabolism; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Molecular Sequence Data; Phagosomes - metabolism; Protein Binding; Protein Interaction Mapping; Protein Transport; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; rab7 GTP-Binding Proteins; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Signal Transduction
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.03.005

Autophagy is an evolutionarily conserved process that enables catabolic and degradative pathways. These pathways commonly depend on vesicular transport controlled by Rabs, small GTPases inactivated by TBC/RabGAPs. The Rac1 effector TBC/RabGAP Armus (TBC1D2A) is known to inhibit Rab7, a key regulator of lysosomal function. However, the precise coordination of signaling and intracellular trafficking that regulates autophagy is poorly understood. We find that overexpression of Armus induces the accumulation of enlarged autophagosomes, while Armus depletion significantly delays autophagic flux. Upon starvation-induced autophagy, Rab7 is transiently activated. This spatiotemporal regulation of Rab7 guanosine triphosphate/guanosine diphosphate cycling occurs by Armus recruitment to autophagosomes via interaction with LC3, a core autophagy regulator. Interestingly, autophagy potently inactivates Rac1. Active Rac1 competes with LC3 for interaction with Armus and thus prevents its appropriate recruitment to autophagosomes. The precise coordination between Rac1 and Rab7 activities during starvation suggests that Armus integrates autophagy with signaling and endocytic trafficking.
[Display omitted]
► Autophagy strongly inactivates Rac1 GTPase and recruits the TBC/RabGAP Armus ► Appropriate Armus localization at autophagosomes requires binding to LC3 ► Armus inhibition delays autophagic flux and increases levels of Rab7·GTP ► Rac1, Armus, and Rab7 coordinate efficient lysosome fusion with autophagosomes
The Rac1 effector Armus is a GTPase-activating protein that regulates Rab7 function and thus endosomal trafficking to lysosomes. Carroll et al. find that Armus binds directly to the core autophagy factor LC3, facilitates fusion of autophagosomes with lysosomes, and integrates local Rac1 activity into the control of autophagy.