Rubicon controls endosome maturation as a Rab7 effector

Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2010; 107(45):19338-43. DOI: 10.1073/pnas.1010554107
Source: PubMed


The activation and recruitment of the small GTPase Rab7 to early endosome is a critical step for early to late endosome maturation, a process that requires the class III phosphatidylinositol 3-kinase (PI3KC3) and GTPase regulators. However, the molecular mechanism underlying Rab7 activation and endosome maturation is still poorly defined. Here we report that Rubicon, a component of the PI3KC3 complex, prevents endosome maturation through differential interactions with Rab7 and UVRAG. UVRAG activates PI3KC3 and C-VPS/HOPS, a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on Rab7. We demonstrate that Rubicon sequesters UVRAG from C-VPS/HOPS. Active GTP-bound Rab7 competes for Rubicon binding and releases UVRAG to associate with C-VPS/HOPS, which in turn promotes further loading of Rab7 with GTP. This feed-forward loop ensures rapid amplification of GTP-bound Rab7 and consequent stimulation of endosome maturation. Hence, Rubicon serves as a previously unknown Rab7 effector to ensure the proper progression of the endocytic pathway.

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    • "RESULTS Arl8b, but not Rab7, interacts with the hVps41 subunit of the HOPS complex in a GTP-dependent manner In our previous study, we identified hVps41 as a direct binding partner for Arl8b, which is recruited to lysosomes in an Arl8b- dependent manner (Garg et al., 2011). However, several reports have implicated a role for Rab7 and/or its effector RILP in regulating late endosomal or lysosomal recruitment of the HOPS complex through interaction with the Vps41 subunit (Sun et al., 2010; van der Kant et al., 2013; Lin et al., 2014). "
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    Full-text · Article · Apr 2015 · Journal of Cell Science
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    • "While the Ambra1-containing complex is required for the induction of autophagy [24], Atg14L/Barkor is thought to function in recruiting the Vps34-Vps15-Atg6 complex to the autophagosomal membrane to initiate autophagosome formation [25]. Rubicon, in contrast, negatively regulates autophagy and endocytosis by preventing the activation of Rab7, a protein that functions in lysosomal fusion and autophagosome maturation [22] [26] [27]. The role of UVRAG in autophagy remains controversial. "
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    Full-text · Article · Apr 2014 · BioMed Research International
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    • "In support of this, the protein Rubicon, which binds to UVRAG and negatively regulates VPS34 activity, inhibits endosomal and autophagosome fusion with lysosomes. Interestingly, active Rab7 displaces the UVRAG– Rubicon interaction, freeing up UVRAG to bind to HOPS complex that, in turn, further activates Rab7[35,36]. Th is provides a strong feed-forward signal to drive the fusion machinery. "
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