PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection

David G McEwan, Benjamin Richter, Beatrice Claudi, Christoph Wigge, Philipp Wild, Hesso Farhan, Kieran McGourty, Fraser Coxon, Mirita Franz-Wachtel, Bram Perdu, Masato Akutsu, Anja Habermann, Anja Kirchof, Miep H Helfrich, Paul R Odgren, Wim Van Hul, Achilleas S Frangakis, Krishnaraj Rajalingam, Boris Macek, David W HoldenDirk Bumann, Ivan Dikic

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)58-71
Number of pages14
JournalCell Host & Microbe
Volume17
Issue number1
Early online date11 Dec 2014
DOIs
Publication statusPublished - 14 Jan 2015

Keywords

  • PLEMKHM1
  • Salmonella
  • Infection
  • biogenesis

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