PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection PMID: 25500191

ADC Targets in Oncology

2026-04-10

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: [email protected].
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: [email protected].

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.