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

38 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

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Vacuoles
Salmonella
Infection
Salmonella enterica
Membranes
GTP Phosphohydrolases
Proteins
Bacteria

Keywords

  • PLEMKHM1
  • Salmonella
  • Infection
  • biogenesis

Cite this

McEwan, D. G., Richter, B., Claudi, B., Wigge, C., Wild, P., Farhan, H., ... Dikic, I. (2015). PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection. Cell Host & Microbe, 17(1), 58-71. https://doi.org/10.1016/j.chom.2014.11.011

PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection. / McEwan, David G; Richter, Benjamin; Claudi, Beatrice; Wigge, Christoph; Wild, Philipp; Farhan, Hesso; McGourty, Kieran; Coxon, Fraser; Franz-Wachtel, Mirita; Perdu, Bram; Akutsu, Masato; Habermann, Anja; Kirchof, Anja; Helfrich, Miep H; Odgren, Paul R; Van Hul, Wim; Frangakis, Achilleas S; Rajalingam, Krishnaraj; Macek, Boris; Holden, David W; Bumann, Dirk; Dikic, Ivan.

In: Cell Host & Microbe, Vol. 17, No. 1, 14.01.2015, p. 58-71.

Research output: Contribution to journalArticle

McEwan, DG, Richter, B, Claudi, B, Wigge, C, Wild, P, Farhan, H, McGourty, K, Coxon, F, Franz-Wachtel, M, Perdu, B, Akutsu, M, Habermann, A, Kirchof, A, Helfrich, MH, Odgren, PR, Van Hul, W, Frangakis, AS, Rajalingam, K, Macek, B, Holden, DW, Bumann, D & Dikic, I 2015, 'PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection', Cell Host & Microbe, vol. 17, no. 1, pp. 58-71. https://doi.org/10.1016/j.chom.2014.11.011
McEwan DG, Richter B, Claudi B, Wigge C, Wild P, Farhan H et al. PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection. Cell Host & Microbe. 2015 Jan 14;17(1):58-71. https://doi.org/10.1016/j.chom.2014.11.011
McEwan, David G ; Richter, Benjamin ; Claudi, Beatrice ; Wigge, Christoph ; Wild, Philipp ; Farhan, Hesso ; McGourty, Kieran ; Coxon, Fraser ; Franz-Wachtel, Mirita ; Perdu, Bram ; Akutsu, Masato ; Habermann, Anja ; Kirchof, Anja ; Helfrich, Miep H ; Odgren, Paul R ; Van Hul, Wim ; Frangakis, Achilleas S ; Rajalingam, Krishnaraj ; Macek, Boris ; Holden, David W ; Bumann, Dirk ; Dikic, Ivan. / PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection. In: Cell Host & Microbe. 2015 ; Vol. 17, No. 1. pp. 58-71.
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AU - Perdu, Bram

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AU - Helfrich, Miep H

AU - Odgren, Paul R

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AU - Frangakis, Achilleas S

AU - Rajalingam, Krishnaraj

AU - Macek, Boris

AU - Holden, David W

AU - Bumann, Dirk

AU - Dikic, Ivan

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N2 - 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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