PLEKHM1 regulates salmonella-containing vacuole biogenesis and infection

David G. McEwan, Benjamin Richter, Beatrice Claudi, Christoph Wigge, Philipp Wild, Hesso Farhan, Kieran McGourty, Fraser P. 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 journalArticlepeer-review

51 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 and Microbe
Volume17
Issue number1
DOIs
Publication statusPublished - 2015 Jan 14
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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