Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella

Kerr, Markus C.; Wang, Jack T. H.; Castro, N.A.; Hamilton, Nicholas A.; Town, Liam; Brown, Darren L.; Meunier, Frédéric A.; Brown, Nathaniel Francis; Stow, Jennifer L.; Teasdale, Rohan D.

doi:10.1038/emboj.2010.28

Cited by 85 publications

(102 citation statements)

References 60 publications

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“…PIKfyve facilitates Rab7a‐independent fusion of LEs with each other and with LYs 30. In addition, the PIKfyve‐activating kinase, Akt, previously implicated in VACV entry 70, 71, was a hit in our screen.…”

Section: Discussionmentioning

confidence: 90%

“…PIKfyve catalyzes the conversion of PtdIns(3)P to PtdIns(3,5)P 2 , a process of importance for the maturation of endosomes and macropinosomes 3, 30, 54. To determine if PIKfyve‐mediated conversion of PtdIns(3)P to PtdIns(3,5)P 2 was important for VACV infection, cells were infected with WR E EGFP MVs in the presence of increasing concentrations of YM201636, an inhibitor of PIKfyve.…”

Section: Resultsmentioning

confidence: 99%

“…As they move deeper into the cytoplasm, macropinosomes acidify and acquire Rab7, Rab21 and lysosome‐associated membrane protein 1 (LAMP1) 26, 27. While there is no consensus as to the final fate of macropinosomes, it has been shown that they can fuse with each other, LEs and LYs, a process that depends on the PI kinase, PIKfyve 26, 28, 29, 30. Thus, the cargo is eventually degraded.…”

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confidence: 99%

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Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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The prototypic poxvirus, vaccinia virus (VACV), occurs in two infectious forms, mature virions (MVs) and extracellular virions (EVs). Both enter HeLa cells by inducing macropinocytic uptake. Using confocal microscopy, live‐cell imaging, targeted RNAi screening and perturbants of endosome maturation, we analyzed the properties and maturation pathway of the macropinocytic vacuoles containing VACV MVs in HeLa cells. The vacuoles first acquired markers of early endosomes [Rab5, early endosome antigen 1 and phosphatidylinositol(3)P]. Prior to release of virus cores into the cytoplasm, they contained markers of late endosomes and lysosomes (Rab7a, lysosome‐associated membrane protein 1 and sorting nexin 3). RNAi screening of endocytic cell factors emphasized the importance of late compartments for VACV infection. Follow‐up perturbation analysis showed that infection required Rab7a and PIKfyve, confirming that VACV is a late‐penetrating virus dependent on macropinosome maturation. VACV EV infection was inhibited by depletion of many of the same factors, indicating that both infectious particle forms share the need for late vacuolar conditions for penetration.

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Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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“…This enables the region of a vesicle to be delineated, and the recruitment and/or expulsion of a fluorescently tagged protein of interest to the vesicle region to be quantified. Several live cell movies showing these dynamic transformations were published by Kerr et al [3]. The four plots of the data are shown in Figure 1.…”

Section: Biomolecular Experimental Data and An Analysis Of A Linear Mmentioning

confidence: 99%

“…Kerr et al [3] describe the experimental details in full. The essence of the approach is to Time lapse videomicroscopy is then performed on individual live cells using a Zeiss LSM 510 meta confocal scanning microscope.…”

Section: Biomolecular Experimental Data and An Analysis Of A Linear Mmentioning

confidence: 99%

Linear models for endocytic transformations from live cell imaging

Belward¹,

Burrage²,

Teasdale³

et al. 2011

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Endocytosis is the process by which cells internalise molecules including nutrient proteins from the extracellular media. In one form, macropinocytosis, the membrane at the cell surface ruffles and folds over to give rise to an internalised vesicle. Negatively charged phospholipids within the membrane called phosphoinositides then undergo a series of transformations that are critical for the correct trafficking of the vesicle within the cell, and which are often pirated by pathogens such as Salmonella. Advanced fluorescent video microscopy imaging now allows the detailed observation and quantification of these events in live cells over time. Here we use these observations as a basis for building differential equation models of the transformations. An initial investigation of these interactions was modelled with reaction rates proportional to the sum of the concentrations of the individual constituents. A first order linear system for the concentrations results. The structure of the system enables analytical expressions to

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Attacking the supply wagons to starve cancer cells to death

et al. 2016

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The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death.

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Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella

Cited by 85 publications

References 60 publications

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Linear models for endocytic transformations from live cell imaging

Attacking the supply wagons to starve cancer cells to death

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