Interaction between the Yersinia protein tyrosine phosphatase YopH and eukaryotic Cas/Fyb is an important virulence mechanism

The tyrosine phosphatase YopH is an essential virulence factor produced by pathogenic Yersinia species. YopH is translocated into host cells via a type III secretion system and its dephosphorylating activity causes disruption of focal complex structures and blockage of the phagocytic process. Among the host cell targets of YopH are the focal adhesion proteins Crk-associated substrate (p130(Cas)) and focal adhesion kinase (FAK) in epithelial cells, and p130(Cas) and Fyn-binding protein (Fyb) in macrophages. Previous studies have shown that the N-terminal domain of YopH acts as a substrate-binding domain. In this study, the mechanism and biological importance of the targeting of YopH to focal complexes relative to its interaction with p130(Cas)/Fyb was elucidated. Mutants of YopH that were defective in p130(Cas)/Fyb binding but otherwise indistinguishable from wild type were constructed. Mutants unable to bind p130(Cas) did not localize to focal complex structures in infected cells, indicating that the association with p130(Cas) is critical for appropriate subcellular localization of YopH. These yopH mutants were also clearly attenuated in virulence, showing that binding to p130(Cas) and/or Fyb is biologically relevant in Yersinia infections.