Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs

The protein fir (translocated intimin receptor) in enteric bacteria shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). Despite the importance of fir in pedestal formation, relatively little is known about the role of fur and its ITIMs in the regulation of the host immune response. Here we demonstrate that fir from enteropathogenic Escherichia coli (EPEC) interacted with the host cellular tyrosine phosphatase SHP-1 in an ITIM phosphorylation dependent manner. The association of fir with SHP-1 facilitated the recruitment of SHP-1 to the adaptor TRAF6 and inhibited the ubiquitination of TRAF6. Moreover, the ITIMs of fir suppressed EPEC-stimulated expression of proinflammatory cytokines and inhibited intestinal immunity to infection with Citrobacter rodentium. Our findings identify a previously unknown mechanism by which bacterial ITIM-containing proteins can inhibit innate immune responses.