Journal
CELL HOST & MICROBE
Volume 17, Issue 1, Pages 58-71Publisher
CELL PRESS
DOI: 10.1016/j.chom.2014.11.011
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Funding
- NICHD
- Flemish FWO [G. 0065.10N]
- Arthritis Research UK [19379]
- Deutsche Forschungsgemeinschaft [DI 931/3-1, DI 931/11-1]
- Cluster of Excellence Macromolecular Complexes of the Goethe University Frankfurt [EXC115]
- LOEWE grant Ub-Net
- LOEWE Centrum for Gene and Cell therapy Frankfurt
- European Research Council/ERC [250241-LineUb]
- Landesstiftung Baden-Wurttemberg Stiftung
- PRIME-XS
- Swiss National Foundation [31003A-121834]
- MRC [MR/J006874/1] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [31003A-121834] Funding Source: Swiss National Science Foundation (SNF)
- Versus Arthritis [20445, 19379] Funding Source: researchfish
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The host endolysosomal compartment is often manipulated by intracellular bacterial pathogens. Salmonella (Salmonella enterica serovar Typhimurium) secrete numerous effector proteins, including SifA, through a specialized type III secretion system to hijack the host endosomal system and generate the Salmonella-containing vacuole (SCV). To form this replicative niche, Salmonella targets the Rab7 GTPase to recruit host membranes through largely unknown mechanisms. We show that Pleckstrin homology domain-containing protein family member 1 (PLEKHM1), a lysosomal adaptor, is targeted by Salmonella through direct interaction with SifA. By binding the PLEKHM1 PH2 domain, Salmonella utilize a complex containing PLEKHM1, Rab7, and the HOPS tethering complex to mobilize phagolysosomal membranes to the SCV. Depletion of PLEKHM1 causes a profound defect in SCV morphology with multiple bacteria accumulating in enlarged structures and significantly dampens Salmonella proliferation in multiple cell types and mice. Thus, PLEKHM1 provides a critical interface between pathogenic infection and the host endolysosomal system.
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