A network of Rab GTPases controls phagosome maturation and is modulated by <i>Salmonella enterica</i> serovar Typhimurium

Smith, Adam C.; Heo, Won Do; Braun, Virginie; Jiang, Xiuju; Macrae, Chloe J.; Casanova, James E.; Scidmore, Marci A.; Grinstein, Sergio; Meyer, Tobias; Brumell, John H.

doi:10.1083/jcb.200611056

Cited by 147 publications

(218 citation statements)

References 28 publications

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“…Greater Sif reductions were observed at longer Sif lengths (Ն15-20 m) but they were not statistically significant. Smith et al report that DNRab9 reduced the percentage of infected cells with Sifs compared to cells expressing CFP alone (16). At longer Sif lengths we do see a decrease in Sifs with DNRab9, but a greater decrease is observed with wild-type Rab9 overexpression.…”

Section: Resultsmentioning

confidence: 69%

“…Because SKIP is central to the maintenance of the SCV, we investigated whether it interacted with other trafficking proteins known to be recruited to the SCV. Specifically, we investigated late endosomal trafficking protein Rab7 and a second late endosomal Rab, Rab9, reported to be found on Sifs (16). Although the location of Rab7 on Sifs is well established, the presence of Rab9 is unexpected because its major cellular cargo, the MPRs, are not found on the SCV to a significant degree (5 To do this, we bound GST fusions of wild-type or constitutively active (Q67L) Rab7 or constitutively active (Q66L) Rab9 proteins that constantly remain in the GTP-bound active state to agarose beads, loaded them with nonhydrolyzable GTP analogue GTP␥S and incubated them with SKIP PH domain protein in pulldown assays.…”

Section: Resultsmentioning

confidence: 99%

“…Rabs and their effectors localize to vacuoles of intracellular pathogens and are important in phagosome trafficking and maintenance (13). The mature SCV interacts with the late endosomal Rabs, Rab7 and Rab9 (13,15,16). Rab7 is important for regulating late endosome to lysosomal transport in cells.…”

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confidence: 99%

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The Salmonella virulence protein SifA is a G protein antagonist

Jackson

Nawabi

Hentea

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Salmonella's success at proliferating intracellularly and causing disease depends on the translocation of a major virulence protein, SifA, into the host cell. SifA recruits membranes enriched in lysosome associated membrane protein 1 (LAMP1) and is needed for growth of Salmonella induced filaments (Sifs) and the Salmonella containing vacuole (SCV). It directly binds a host protein called SKIP (SifA and kinesin interacting protein) which is critical for membrane stability and motor dynamics at the SCV. SifA also contains a WxxxE motif, predictive of G protein mimicry in bacterial effectors, but whether and how it mimics the action of a host G protein is not known. We show that SKIP's pleckstrin homology domain, which directly binds SifA, also binds to the late endosomal GTPase Rab9. Knockdown studies suggest that both SKIP and Rab9 function to maintain peripheral LAMP1 distribution in cells. The Rab9:SKIP interaction is GTP-dependent and is inhibited by SifA binding to the SKIP pleckstrin homology domain, suggesting that SifA may be a Rab9 antagonist. SifA:SKIP binding is significantly tighter than Rab9:SKIP binding and may thus allow SifA to bring SKIP to the SCV via SKIP's Rab9-binding site. Rab9 can measurably reverse SifA-dependent LAMP1 recruitment and the perinuclear location of the SCV in cells. Importantly, binding to SKIP requires SifA residues W197 and E201 of the conserved WxxxE signature sequence, leading to the speculation that bacterial G protein mimicry may result in G protein antagonism.GTPase ͉ LAMP1 ͉ Rab9 ͉ SKIP ͉ lysosome

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Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The Salmonella virulence protein SifA is a G protein antagonist

Jackson

Nawabi

Hentea

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Multiple Rab proteins are associated with phagosomes regulating the interactions of these organelles with endosomes and lysosomes (5)(6)(7)(8). Many of these phagosomal Rab proteins are even recruited at the same time, although in some cases the kinetics is different (7,9).…”

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confidence: 99%

Size-dependent mechanism of cargo sorting during lysosome-phagosome fusion is controlled by Rab34

Kasmapour

Gronow

Bleck

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Phagosome maturation is an essential part of the innate and adaptive immune response. Although it is well established that several Ras-related proteins in brain (Rab) proteins become associated to phagosomes, little is known about how these phagosomal Rab proteins influence phagosome maturation. Here, we show a specific role for Rab34 and mammalian uncoordinated 13-2 (Munc13-2) in phagolysosome biogenesis and cargo delivery. Rab34 knockdown impaired the fusion of phagosomes with late endosomes/lysosomes and high levels of active Rab34 promoted this process. We demonstrate that Rab34 enhances phagosome maturation independently of Rab7 and coordinates phagolysosome biogenesis through sizeselective transfer of late endosomal/lysosomal cargo into phagosomes. More importantly, we show that Rab34 mediates phagosome maturation through the recruitment of the protein Munc13-2. Finally, we report that the alternative maturation pathway controlled by Rab34 is critical for mycobacterial killing because Rab34 silencing resulted in mycobacterial survival, and Rab34 expression led to mycobacterial killing. Altogether, our studies uncover Rab34/ Munc13-2 as a critical part of an alternative Rab7-independent phagosome maturation machinery and lysosome-mediated killing of mycobacteria.

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“…15,16 Rab32 and Rab38 participate in the generation and traffic of melanosomes, 17 while Rab29 regulates retrograde endolysosome-to-Golgi trafficking of the mannose-6-phosphate receptor (MPR) in epithelial and neuronal cells. 18,19 Based on the implication of Rab29 in typhoid toxin trafficking to the plasma membrane from the SCV, 15 where Rab4 and Rab11 have also been observed, 20 here we assessed the role of Rab29 in the regulation of TCR recycling. The results identify Rab29 as a novel regulator of vesicular trafficking in T cells, acting as a complex with IFT20 and the Rabs Rab8 and Rab11 to control TCR recycling and IS assembly.…”

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confidence: 99%

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

et al. 2015

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Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11 + endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly. T-cell activation is triggered by T-cell antigen receptor (TCR) engagement by MHC-bound peptide dispayed by an antigen presenting cell (APC). While a substantial proportion of the TCR has long been known to be associated with recycling endosomes, 1 it is only recently that the central function of this pool has emerged with the finding that, on assembly of the specialized interface with the APC, known as the immune synapse (IS), intracellular TCRs are delivered to this location by polarized recycling. 2 This process ensures a steady supply of TCRs at the IS to sustain signaling for T-cell activation 3 and has been co-opted by other receptors, such as the transferrin receptor (TfR) and the chemokine receptor CXCR4, 4,5 as well as membrane-bound signaling mediators, such as the kinase Lck and the adaptor LAT. 6,7 Receptor recycling is orchestrated by the small GTPases Rab4 and Rab11. 8 Cargo specificity is achieved with the assistance of specific regulators and effectors. The TCR recycling pathway has only started to be delineated with the identification of specific mediators, which include Rab35 and its GAP EPI64C 9 and the actin adaptor WASH 10 . Specific combinations of Rabs and SNAREs have been recently associated with recycling endosomes carrying either Lck, or TCRζ and LAT. 11 We have moreover identified IFT20 12 and other components of the intraflagellar transport (IFT) system, which regulates ciliary assembly and function, 13 as unexpected regulators of TCR recycling in the non-ciliated T cell. 14 Recently a Rab GTPase subfamily, which includes Rab29, Rab32 and Rab38, has been implicated in trafficking of the Salmonella-containing vacuole (SCV) in infected epithelial cells. 15,16 Rab32 and Rab38 ...

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A network of Rab GTPases controls phagosome maturation and is modulated by Salmonella enterica serovar Typhimurium

Cited by 147 publications

References 28 publications

The Salmonella virulence protein SifA is a G protein antagonist

The Salmonella virulence protein SifA is a G protein antagonist

Size-dependent mechanism of cargo sorting during lysosome-phagosome fusion is controlled by Rab34

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

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