8.A.223.  The Translocated Intimin Receptor (TIR) Family 

Tir is a multifunctional protein that is required for efficient pedestal formation in host epithelial cells during bacterial infection. The extracellular region acts as a receptor for bacterial intimin, allowing the bacterium to attach tightly to the host-cell surface. Simultaneously, the intracellular region initiates a signaling cascade in the host cell, which leads to actin polymerization and formation of actin pedestals at the sites of bacterial adhesion. In strain E2348/69, it acts mainly via the host adaptor proteins NCK1 and NCK2. Once clustered and phosphorylated at Tyr-474, Tir binds to NCK proteins, which in turn bind and activate host WASL/N-WASP, leading to actin polymerization. It can also trigger inefficiently, NCK-independent pedestal formation. This pathway involves phosphorylation of Tyr-454 and probably a putative host adaptor. Tir acts also via direct binding to the host cytoskeletal protein, alpha-actinin, in a NCK- and phosphotyrosine-independent manner. This interaction may stabilize the pedestal, but is not essential for its formation (Kenny 1999).  The transmembrane domains of the type III secretion system effector Tir are involved in its secretion and cellular activities (Braverman et al. 2023). 

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