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Cell Host Microbe. 2015 Jan 14;17(1):58-71. doi: 10.1016/j.chom.2014.11.011. Epub 2014 Dec 11.

PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection.

Author information

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.

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.

PMID:
25500191
DOI:
10.1016/j.chom.2014.11.011
[Indexed for MEDLINE]
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