title: Mycobacterium tuberculosis suppresses innate immunity by coopting the host ubiquitin system.
abstract: 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.
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Jing
authors: J
authors: Wang
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Bing-Xi
authors: BX
authors: Li
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Pu-Pu
authors: PP
authors: Ge
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Jie
authors: J
authors: Li
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Qi
authors: Q
authors: Wang
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: George Fu
authors: GF
authors: Gao
authors: Ministry of Education, Key Laboratory of Cell Proliferation and Regulation Biology, Department of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
authors: Xiao-Bo
authors: XB
authors: Qiu
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors: Cui Hua
authors: CH
authors: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology; D020298:U937 Cells; D025801:Ubiquitin / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C481053:TAB3 protein, human; D025801:Ubiquitin
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