Sequestering of Rac by the Yersinia Effector YopO Blocks Fcγ 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 Fc gamma 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 RhoGDI alpha. We propose that YopO exploits this basic difference in localization and availability to selectively inhibit Rac-dependent phagocytosis.