Sequestering of Rac by the Yersinia effector YopO blocks Fcgamma receptor-mediated phagocytosis.
Pathogenic Yersinia species neutralize innate immune mechanisms by injecting type three secretion effectors into immune cells, altering cell signaling. Our study elucidates how one of these effectors, YopO, blocks phagocytosis. We demonstrate using different phagocytic models that YopO specifically blocks Rac-dependent Fcgamma receptor internalization pathway but not complement receptor 3-dependent uptake, which is controlled by Rho activity. We show that YopO prevents Rac activation but does not affect Rac accumulation at the phagocytic cup. In addition, we show that plasma membrane localization and the guanine-nucleotide dissociation inhibitor (GDI)-like domain of YopO cooperate for maximal anti-phagocytosis. Although YopO has the same affinity for Rac1, Rac2, and RhoA in vitro, it selectively interacts with Rac isoforms in cells. This is due to the differential localization of the Rho family G proteins in resting cells; Rac isoforms partially exist as a GDI-free pool at the membrane of resting cells, whereas RhoA is trapped in the cytosol by RhoGDIalpha. We propose that YopO exploits this basic difference in localization and availability to selectively inhibit Rac-dependent phagocytosis.
Groves
Eleanor
E
From the Centre for Molecular Microbiology and Infection, Imperial College London, London SW7 2AZ, United Kingdom. Electronic address: e.groves@imperial.ac.uk.
Rittinger
Katrin
K
the Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, London NW7 1AA, United Kingdom, and.
Amstutz
Marlise
M
Infection Biology, Biozentrum, University of Basel, Klingenbergstrasse 50/70, CH-4056 Basel, Switzerland.
Berry
Sara
S
From the Centre for Molecular Microbiology and Infection, Imperial College London, London SW7 2AZ, United Kingdom.
Holden
David W
DW
From the Centre for Molecular Microbiology and Infection, Imperial College London, London SW7 2AZ, United Kingdom.
Cornelis
Guy R
GR
Infection Biology, Biozentrum, University of Basel, Klingenbergstrasse 50/70, CH-4056 Basel, Switzerland.
Caron
Emmanuelle
E
From the Centre for Molecular Microbiology and Infection, Imperial College London, London SW7 2AZ, United Kingdom.
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D010587:Phagocytosis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015008:Yersinia enterocolitica / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; C080568:Fc gamma receptor IIA; C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D017452:Receptors, IgG; D049452:Green Fluorescent Proteins; C415206:YopO protein, Yersinia enterocolitica; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein