PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection

Cell Host Microbe. 2015 Jan 14;17(1):58-71. doi: 10.1016/j.chom.2014.11.011.

David G McEwan ¹, Benjamin Richter ¹, Beatrice Claudi ², Christoph Wigge ³, Philipp Wild ¹, Hesso Farhan ⁴, Kieran McGourty ⁵, Fraser P Coxon ⁶, Mirita Franz-Wachtel ⁷, Bram Perdu ⁸, Masato Akutsu ², Anja Habermann ³, Anja Kirchof ¹, Miep H Helfrich ⁶, Paul R Odgren ⁹, Wim Van Hul ⁸, Achilleas S Frangakis ², Krishnaraj Rajalingam ¹⁰, Boris Macek ⁷, David W Holden ⁵, Dirk Bumann ¹¹, Ivan Dikic ¹²

Affiliations

1 Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
2 Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland.
3 Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany.
4 Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland; Biotechnology Institute Thurga, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
5 Centre for Molecular Microbiology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
6 Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
7 Proteome Center Tübingen, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
8 Department of Medical Genetics, University of Antwerp, Prins Boudewijnlaan 43B, 2650 Edegem, Belgium.
9 Deptartment of Cell Biology, S7-242, University of Massachusetts Medical School, North Worcester, MA 01655, USA.
10 Molecular Signaling Unit, FZI, Institute for immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, Mainz 55131, Germany.
11 Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland. Electronic address: dirk.bumann@unibas.ch.
12 Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany; Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany; University of Split, School of Medicine, Department of Immunology and Medical Genetics, Soltanska 2, 21 000 Split, Croatia. Electronic address: Ivan.Dikic@biochem2.de.

PMID: 25500191 DOI: 10.1016/j.chom.2014.11.011

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.

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