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 signalling. Our study elucidates how one of these effectors, YopO, blocks phagocytosis. We demonstrate using different phagocytic models that YopO specifically blocks Rac-dependent FcgammaR-internalisation pathway but not CR3-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 localisation and the GDI-like domain of YopO cooperate for maximal anti-phagocytosis. While 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 localisation 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 localisation and availability to selectively inhibit Rac-dependent phagocytosis.