TY - JOUR
T1 - PLEKHM1 regulates salmonella-containing vacuole biogenesis and infection
AU - McEwan, David G.
AU - Richter, Benjamin
AU - Claudi, Beatrice
AU - Wigge, Christoph
AU - Wild, Philipp
AU - Farhan, Hesso
AU - McGourty, Kieran
AU - Coxon, Fraser P.
AU - Franz-Wachtel, Mirita
AU - Perdu, Bram
AU - Akutsu, Masato
AU - Habermann, Anja
AU - Kirchof, Anja
AU - Helfrich, Miep H.
AU - Odgren, Paul R.
AU - Van Hul, Wim
AU - Frangakis, Achilleas S.
AU - Rajalingam, Krishnaraj
AU - Macek, Boris
AU - Holden, David W.
AU - Bumann, Dirk
AU - Dikic, Ivan
N1 - Funding Information:
We would like to acknowledge Anja Bremm and Margaret Frame for critical reading of the manuscript and valuable insights. We would like to thank S. Wahl and J. Madlung for sample preparation and MS measurement. The mCherry-LAMP1 was a kind gift from J. Lippincott-Schwartz, and the SifA and SKIP construct was a generous gift from S. Meresse. The anti-LAMP1 and LAMP2 antibody developed by J.T. August was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology. K.R. is a Heisenberg professor of the DFG (RA1739/4-1), a BIS-PLUS3 fellow, and a GRC fellow. This work was supported by grants from the Flemish FWO G.0065.10N to W.V.H., Arthritis Research UK (grant number 19379) to F.P.C. and M.H.H., Deutsche Forschungsgemeinschaft (DI 931/3-1; DI 931/11-1), the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC115), LOEWE grant Ub-Net and LOEWE Centrum for Gene and Cell therapy Frankfurt, and the European Research Council/ERC grant agreement n° 250241-LineUb to I.D.; Landesstiftung Baden-Württemberg Stiftung and PRIME-XS to B.M. and Swiss National Foundation (31003A-121834), SystemsX.ch (RTD project “BattleX”) to D.B.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/1/14
Y1 - 2015/1/14
N2 - 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.
AB - 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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U2 - 10.1016/j.chom.2014.11.011
DO - 10.1016/j.chom.2014.11.011
M3 - Article
C2 - 25500191
AN - SCOPUS:84920984853
VL - 17
SP - 58
EP - 71
JO - Cell Host and Microbe
JF - Cell Host and Microbe
SN - 1931-3128
IS - 1
ER -