Many pathogens infect hosts through various immune evasion strategies. However, the molecular mechanisms by which pathogen proteins modulate and evade the host immune response remain unclear. Enterohemorrhagic Escherichia coli (EHEC) is a pathological strain that can induce mitogen-activated protein (MAP) kinase (Erk, Jnk and p38 MAPK) and NE-kappa B pathway activation and proinflammatory cytokine production, which then causes diarrheal diseases such as hemorrhagic colitis and hemolytic uremic syndrome. Transforming growth factor beta-activated kinase-1 (TAK1) is a key regulator involved in distinct innate immune signalling pathways. Here we report that EHEC translocated intimin receptor (Tir) protein inhibits the expression of EHEC-induced proinflammatory cytokines by interacting with the host tyrosine phosphatase SHP-1, which is dependent on the phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction. Taken together, these results suggest that EHEC Tir negatively regulates proinflammatory responses by inhibiting the activation of TAK1, which is essential for immune evasion and could be a potential target for the treatment of bacterial infection.
[1]Fudan Univ, Dept Immunol, Sch Basic Med Sci, Shanghai 200032, Peoples R China;
[2]Fudan Univ, Shanghai Publ Hlth Clin Ctr, Key Lab Med Mol Virol MOE MOH, Shanghai 200032, Peoples R China;
[3]Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing, Peoples R China;
[4]Tianjin Med Univ, Sch Biomed Engn, Tianjin, Peoples R China;
[5]Tongji Univ, Sch Med, Shanghai Key Lab TB, Shanghai Pulm Hosp, Shanghai, Peoples R China;
[6]Tongji Univ, Sch Med, Dept Microbiol & Immunol, Shanghai, Peoples R China
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