Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella |
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| Authors: | Markus C Kerr Jack T H Wang Natalie A Castro Nicholas A Hamilton Liam Town Darren L Brown Frederic A Meunier Nat F Brown Jennifer L Stow Rohan D Teasdale |
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| Affiliation: | 1. Institute for Molecular Bioscience and ARC Centre of Excellence in Bioinformatics, The University of Queensland, St Lucia, Queensland, Australia;2. Molecular Dynamics of Synaptic Function Laboratory, Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia;3. Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia |
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| Abstract: | 3‐phosphorylated phosphoinositides (3‐PtdIns) orchestrate endocytic trafficking pathways exploited by intracellular pathogens such as Salmonella to gain entry into the cell. To infect the host, Salmonellae subvert its normal macropinocytic activity, manipulating the process to generate an intracellular replicative niche. Disruption of the PtdIns(5) kinase, PIKfyve, be it by interfering mutant, siRNA‐mediated knockdown or pharmacological means, inhibits the intracellular replication of Salmonella enterica serovar typhimurium in epithelial cells. Monitoring the dynamics of macropinocytosis by time‐lapse 3D (4D) videomicroscopy revealed a new and essential role for PI(3,5)P2 in macropinosome‐late endosome/lysosome fusion, which is distinct from that of the small GTPase Rab7. This PI(3,5)P2‐dependent step is required for the proper maturation of the Salmonella‐containing vacuole (SCV) through the formation of Salmonella‐induced filaments (SIFs) and for the engagement of the Salmonella pathogenicity island 2‐encoded type 3 secretion system (SPI2‐T3SS). Finally, although inhibition of PIKfyve in macrophages did inhibit Salmonella replication, it also appears to disrupt the macrophage's bactericidal response. |
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| Keywords: | endocytosis macropinocytosis phosphoinositide PIKfyve Salmonella |
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