Mycobacterium tuberculosis suppresses innate immunity by coopting the host ubiquitin system.
Mycobacterium tuberculosis PtpA, a secreted tyrosine phosphatase essential for tuberculosis pathogenicity, could be an ideal target for a drug against tuberculosis, but its active-site inhibitors lack selectivity over human phosphatases. Here we found that PtpA suppressed innate immunity dependent on pathways of the kinases Jnk and p38 and the transcription ... factor NF-κB by exploiting host ubiquitin. Binding of PtpA to ubiquitin via a region with no homology to human proteins activated it to dephosphorylate phosphorylated Jnk and p38, leading to suppression of innate immunity. Furthermore, the host adaptor TAB3 mediated NF-κB signaling by sensing ubiquitin chains, and PtpA blocked this process by competitively binding the ubiquitin-interacting domain of TAB3. Our findings reveal how pathogens subvert innate immunity by coopting host ubiquitin and suggest a potential tuberculosis treatment via targeting of ubiquitin-PtpA interfaces.
Mesh Terms:
Animals, Cell Line, Cell Line, Tumor, Female, HEK293 Cells, HeLa Cells, Humans, Immunity, Innate, Intracellular Signaling Peptides and Proteins, Male, Mice, Inbred C57BL, Mycobacterium tuberculosis, NF-kappa B, Phosphorylation, Signal Transduction, Tuberculosis, U937 Cells, Ubiquitin
Animals, Cell Line, Cell Line, Tumor, Female, HEK293 Cells, HeLa Cells, Humans, Immunity, Innate, Intracellular Signaling Peptides and Proteins, Male, Mice, Inbred C57BL, Mycobacterium tuberculosis, NF-kappa B, Phosphorylation, Signal Transduction, Tuberculosis, U937 Cells, Ubiquitin
Nat. Immunol.
Date: Mar. 01, 2015
PubMed ID: 25642820
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