PLEKHM1 Regulates Salmonella-Containing Vacuole Biogenesis and Infection

• Published in: Cell host & microbe Vol. 17; no. 1; pp. 58 - 71
• Main Authors: McEwan, David G., Richter, Benjamin, Claudi, Beatrice, Wigge, Christoph, Wild, Philipp, Farhan, Hesso, McGourty, Kieran, Coxon, Fraser P., 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.01.2015
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Autophagy-Related Proteins; Bacterial Proteins - metabolism; Carrier Proteins - metabolism; Glycoproteins - metabolism; Host-Pathogen Interactions; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins - metabolism; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins - metabolism; Protein Binding; Protein Interaction Mapping; rab GTP-Binding Proteins - metabolism; Salmonella typhimurium - growth & development; Vacuoles - microbiology
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.11.011

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. [Display omitted] •PLEKHM1 loss impairs Salmonella proliferation and vacuole formation•PLEKHM1 simultaneously interacts with Salmonella effector SifA and Rab7 via a PH2 domain•SifA recruits the PLEKHM1/Rab7/HOPS complex for SCV maintenance Salmonella hijack the lysosomal compartment to provide a stable intracellular proliferative niche. McEwan et al. show that the Salmonella effector SifA recruits the HOPS complex and Rab7 through PLEKHM1. Loss of PLEKHM1 decreases Salmonella proliferation and alters vacuole structure, leading to multiple Salmonella encased in enlarged structures.