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

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...

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Bibliographic Details
Published in:Developmental cell 2013-04, Vol.25 (1), p.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: Article
Language:English
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
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Summary: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.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2013.03.005