CBL-C E3 ubiquitin ligase acts as a host defense to mediate ubiquitin-proteasomal degradation of enteropathogenic Escherichia coli Tir protein

Translocated intimin receptor (Tir) is an essential bacterial factor for enteropathogenic Escherichia coli (EPEC) to establish Tir-intimin interaction-mediated adherence to the epithelial cell and to form actin pedestal structures beneath the adherent bacteria. However, it remains unclear how the host cells eliminate Tir protein after infection. Here we show that intracellular translocated Tir is degraded via the host ubiquitin- proteasome system. We found that host CBL-C, an E3 ubiquitin-protein ligase, bound to and ubiquitinated the 454 tyrosine-phosphorylated Tir protein. Tir ubiquitination leads to proteasome-dependent degradation and attenuated EPEC colonization of the epithelial cell. Using Citrobacter rodentium , a mouse model for EPEC, we demonstrated that infection with C . rodentium mutant expressing a tyrosine- phenylalanine-substituted Tir (CBL-C resistant) showed increased bacterial loads in the colon and lethality compared with infection with C . rodentium expressing wild-type Tir. These results indicate that CBL-C is a critical host defense factor that determines the fate of cytosolic Tir and terminates bacterial colonization. ![Figure][1] Graphical Abstracts ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes