title: The TBC/RabGAP Armus coordinates Rac1 and Rab7 functions during autophagy.
abstract: 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.
authors.affiliation: Molecular Medicine, NHLI, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Carroll
authors.forename: Noor
authors.initials: N
authors.lastname: Mohd-Naim
authors.forename: Filipe
authors.initials: F
authors.lastname: Maximiano
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Frasa
authors.forename: Jessica
authors.initials: J
authors.lastname: McCormack
authors.forename: Mattea
authors.initials: M
authors.lastname: Finelli
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Thoresen
authors.forename: Louis
authors.initials: L
authors.lastname: Perdios
authors.forename: Reiko
authors.initials: R
authors.lastname: Daigaku
authors.forename: Richard E
authors.initials: RE
authors.lastname: Francis
authors.forename: Clare
authors.initials: C
authors.lastname: Futter
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Vania M M
authors.initials: VM
authors.lastname: Braga
mesh_terms: D000595:Amino Acid Sequence; D001343:Autophagy; D003470:Culture Media / Q000378:metabolism; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D003470:Culture Media; D020690:GTPase-Activating Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C107953:RAC1 protein, human; C549113:TBC1D2 protein, human; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D006160:Guanosine Triphosphate; D020691:rab GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
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