title: PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection.
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.
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: David G
authors.initials: DG
authors.lastname: McEwan
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Richter
authors.affiliation: Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Claudi
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wigge
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wild
authors.affiliation: Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland; Biotechnology Institute Thurga, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
authors.forename: Hesso
authors.initials: H
authors.lastname: Farhan
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors.forename: Kieran
authors.initials: K
authors.lastname: McGourty
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
authors.affiliation: Proteome Center Tübingen, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Mirita
authors.initials: M
authors.lastname: Franz-Wachtel
authors.affiliation: Department of Medical Genetics, University of Antwerp, Prins Boudewijnlaan 43B, 2650 Edegem, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Perdu
authors.affiliation: Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland.
authors.forename: Masato
authors.initials: M
authors.lastname: Akutsu
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, Goethe University 60438 Frankfurt am Main, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Habermann
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kirchof
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
authors.affiliation: Deptartment of Cell Biology, S7-242, University of Massachusetts Medical School, North Worcester, MA 01655, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Odgren
authors.affiliation: Department of Medical Genetics, University of Antwerp, Prins Boudewijnlaan 43B, 2650 Edegem, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.affiliation: Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland.
authors.forename: Achilleas S
authors.initials: AS
authors.lastname: Frangakis
authors.affiliation: Molecular Signaling Unit, FZI, Institute for immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, Mainz 55131, Germany.
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Rajalingam
authors.affiliation: Proteome Center Tübingen, Interfaculty Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Macek
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Holden
authors.affiliation: Infection Biology, Biozentrum, University Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland. Electronic address: dirk.bumann@unibas.ch.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bumann
authors.affiliation: 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.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000071183:Autophagy-Related Proteins; D001426:Bacterial Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012486:Salmonella typhimurium / Q000254:growth & development*; D014617:Vacuoles / Q000382:microbiology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; C531356:HOPS protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C476215:PLEKHM1 protein, human; C421862:SifA protein, Salmonella; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins