Abstract
Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-β-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.
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Data availability
The data that support the findings of this study are available from the corresponding author on request.
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Acknowledgements
We thank J. Chen (The University of Texas Southwestern Medical Center) for TAK1 condition knockout mice. We thank L.-D. Lyu (CAS Key Laboratory of Synthetic Biology) for technical discussions on MPT53 knockout strain construction. We thank K. Mi (CAS Key Laboratory of Pathogenic Microbiology and Immunology) for providing the pMV261 plasmid. We thank the members of the B. Ge laboratory for their helpful discussions and technical assistance. This project was supported by grants from Chinese National Program on Key Basic Research Project (grant no. 2017YFA0505900), National Natural Science Foundation of China (grant nos 91842303 and 31730025 to B.G. and grant no. 81800004 to L.W.) and Fundamental Research Funds for the Central Universities (grant no. 22120180024).
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L.W. and B.G designed this study. L.W. and Z.L. performed most of the experiments and analysed data, assisted by H.Liu, J.Wu, T.T., H.Li, D.M., J.Chen, F.L., R.Z., P.S., Y.Z., X.W., H.Lang, S.Z. and J.Cao. J.Wang constructed the knockout H37Rv strain, assisted by H.Y., L.Q. and X.H. Z.C. constructed recombinant M. smegmatis. C.W. provided clinical samples. X.C. and G.Z. provided helpful discussions and assisted with the manuscript preparation. Y.C. and D.S. provided the structure analysis. All authors discussed the results and commented on the manuscript.
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Wang, L., Liu, Z., Wang, J. et al. Oxidization of TGFβ-activated kinase by MPT53 is required for immunity to Mycobacterium tuberculosis. Nat Microbiol 4, 1378–1388 (2019). https://doi.org/10.1038/s41564-019-0436-3
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DOI: https://doi.org/10.1038/s41564-019-0436-3
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