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

Abstract

SummaryAutophagy 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.

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

“…4D), similar to the Armus and LC3 colocalization previously reported ( Fig. 4D) (Carroll et al, 2013).…”

“…Rab7 regulates the homotypic fusion of late endosomes and the heterotypic fusion of late endosomes with lysosomes (Kümmel and Ungermann, 2014). Although previous work has established a role for Armus in regulating Rab7 activity during autophagy and mitophagy, we believe our findings support a role for Armus-regulated Rab7 activity in the late endocytic pathway (Carroll et al, 2013;Yamano et al, 2014). Our previous work characterizing the Vps34 −/− MEFs established that the autophaghic pathway is defective in these cells, beginning from the early stages of autophagosome biogenesis (Jaber et al, 2012).…”

“…Armus and TBC1D15 act as Rab7 GAPs, whereas the Mon1-Ccz1 complex (note that there are two isoforms of Mon1, Mon1a and Mon1b, in mammals) acts as a Rab7 GEF (Gerondopoulos et al, 2012;Nordmann et al, 2010;Yasuda et al, 2016). In addition to endocytic trafficking, these regulators play important roles in autophagy: Armus (also known as TBC1D2) is a Rac1 effector that interacts with LC3 (MAP1LC3A) proteins to regulate Rab7-GTP levels on autophagosomes (Carroll et al, 2013), TBC1D15 interacts with LC3 to regulate Rab7 activity during mitophagy (Yamano et al, 2014), and Mon1-Ccz1 is required for autophagosomelysosome fusion (Hegedus et al, 2016).…”

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

“…PIK3C3/VPS34 deficiency prevents recruitment of TBC1D2/Armus (the RAB7-specific GTPase activation protein) to endosomal membranes. TBC1D2 interacts with LC3 and regulates RAB7-GTP hydrolysis selectively on autophagosomes to enable fusion with lysosomes and subsequent degradation of the transported cargo [53]. Thus, higher amounts of RAB7-GTP in B. cenocepacia -infected casp4 −/- macrophages may be attributed to decreased GTPase activity around the B. cenocepacia -containing vacuoles.…”

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

“…33 , 34 Notably, RAB7 regulates autophagosomal maturation controlling the final step of maturation of late autophagic vesicles into autolysosomes, presumably involving fusion with lysosomes. 12 , 35–37 …”