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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    • "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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    ABSTRACT: The interconnection of the endocytic and autophagosomal trafficking routes has been recognized more than two decades ago with both pathways using a set of identical effector proteins and sharing the same ultimate lysosomal destination. More recent data sheds light onto how other pathways are intertwined into this network, and how degradation via the endosomal/autophagosomal system may affect signaling pathways in multicellular organisms. Here, we briefly review the common features of autophagy and endocytosis and discuss how other players enter this mix with particular respect to the Notch signaling pathway.
    BioMed Research International 04/2014; 2014:960803. DOI:10.1155/2014/960803 · 2.71 Impact Factor
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    • "In support of this view, we found that disruption of the C/VPS complex binding site prevents UVRAG from Rab7 activation and inducing endosome fusion (Liang et al., 2008). This view is further reinforced in the work by Sun et al. (2010), which showed that UVRAG acts in concert with Rab7 and the negative regulator Rubicon to balance the endocytic vesicles' flux. It appears that the Rubicon protein sequesters UVRAG from the C/VPS complex interaction, wherease activated Rab7 releases UVRAG from Rubicon inhibition and promotes the UVRAG–C/VPS complex assembly, which in turn activates more Rab7 for endosome maturation. "
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    ABSTRACT: Functional inactivation of UVRAG is implicated in common human cancers. It was originally accepted that UVRAG functions as a promoter of the autophagy pathway by forming a stable complex with Beclin 1. However, recent studies have highlighted novel non-autophagic roles of UVRAG, and these reports indi- cate that UVRAG is much more versatile than we originally expected. In addition to regulating catabolic autophagy, UVRAG is also involved in regulating endosomal membrane trafficking, repairing DNA lesions, patrolling the centrosome, and preventing apoptosis. These studies are beginning to shed light on the com- plexity and cross-talk between the signaling networks involving UVRAG, which normally control diverse cellular processes, and how disruption of these networks leads to tumor formation.
    Edited by M. A. Hayat, 09/2013; Elsevier., ISBN: 9780124115149
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    • "We showed that Rubicon efficiently facilitates the phagosomal trafficking of the p22phox- gp91phox complex in a binding-dependent manner. Recent studies have shown that Rubicon interacts with the Rab7 GTPase protein through its C-terminal cysteine-rich domain (Sun et al., 2010). Because Rab7 regulates membrane trafficking by cycling between inactive (i.e., GDP-bound) and active (i.e., GTP-bound) states, the Rubicon-Rab7 interaction is likely involved in facilitating the phagosome recruitment of the p22phox-gp91phox complex. "
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    ABSTRACT: Phagocytosis and autophagy are two important and related arms of the host's first-line defense against microbial invasion. Rubicon is a RUN domain containing cysteine-rich protein that functions as part of a Beclin-1-Vps34-containing autophagy complex. We report that Rubicon is also an essential, positive regulator of the NADPH oxidase complex. Upon microbial infection or Toll-like-receptor 2 (TLR2) activation, Rubicon interacts with the p22phox subunit of the NADPH oxidase complex, facilitating its phagosomal trafficking to induce a burst of reactive oxygen species (ROS) and inflammatory cytokines. Consequently, ectopic expression or depletion of Rubicon profoundly affected ROS, inflammatory cytokine production, and subsequent antimicrobial activity. Rubicon's actions in autophagy and in the NADPH oxidase complex are functionally and genetically separable, indicating that Rubicon functions in two ancient innate immune machineries, autophagy and phagocytosis, depending on the environmental stimulus. Rubicon may thus be pivotal to generating an optimal intracellular immune response against microbial infection.
    Cell host & microbe 03/2012; 11(3):264-76. DOI:10.1016/j.chom.2012.01.018 · 12.33 Impact Factor
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