Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Oxidization of TGFβ-activated kinase by MPT53 is required for immunity to Mycobacterium tuberculosis

Nature Microbiology volume 4, pages 1378–1388 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MPT53 activates host inflammation responses.
Fig. 2: MPT53 interacts with TAK1.
Fig. 3: MPT53 activates TAK1.
Fig. 4: MPT53 triggers inflammation via disulfide oxidoreductase activity.
Fig. 5: MPT53 promotes the formation of TAK1 disulfide bonds at C210.
Fig. 6: MPT53 activates inflammation through the oxidation of TAK1 at C210.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author on request.

References

  1. Kaufmann, S. H. E. et al. Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir. Med. 2, 301–320 (2014).

    Article  CAS  Google Scholar 

  2. World Health Organization. WHO Global Tuberculosis Report 2018 (WHO, 2018).

  3. Ottenhoff, T. H. & Kaufmann, S. H. E. Vaccines against tuberculosis: where are we and where do we need to go? PLoS Pathog. 8, e1002607 (2012).

    Article  CAS  Google Scholar 

  4. Khan, N., Vidyarthi, A., Javed, S. & Agrewala, J. N. Innate immunity holding the flanks until reinforced by adaptive immunity against Mycobacterium tuberculosis infection. Front. Microbiol. 7, 328 (2016).

    PubMed  PubMed Central  Google Scholar 

  5. Mayer-Barber, K. D. & Sher, A. Cytokine and lipid mediator networks in tuberculosis. Immunol. Rev. 264, 264–275 (2015).

    Article  CAS  Google Scholar 

  6. Ernst, J. D. The immunological life cycle of tuberculosis. Nat. Rev. Immunol. 12, 581–591 (2012).

    Article  CAS  Google Scholar 

  7. O’Garra, A. et al. The immune response in tuberculosis. Annu. Rev. Immunol. 31, 475–527 (2013).

    Article  Google Scholar 

  8. Robinson, R. T., Orme, I. M. & Cooper, A. M. The onset of adaptive immunity in the mouse model of tuberculosis and the factors that compromise its expression. Immunol. Rev. 264, 46–59 (2015).

    Article  CAS  Google Scholar 

  9. Hmama, Z., Pena-Diaz, S., Joseph, S. & Av-Gay, Y. Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis. Immunol. Rev. 264, 220–232 (2015).

    Article  CAS  Google Scholar 

  10. Liu, C. H., Liu, H. & Ge, B. Innate immunity in tuberculosis: host defense vs pathogen evasion. Cell. Mol. Immunol. 14, 963–975 (2017).

    Article  CAS  Google Scholar 

  11. Dorhoi, A. & Kaufmann, S. H. E. Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis. Semin. Immunopathol. 38, 153–166 (2016).

    Article  CAS  Google Scholar 

  12. Huynh, K. K., Joshi, S. A. & Brown, E. J. A delicate dance: host response to mycobacteria. Curr. Opin. Immunol. 23, 464–472 (2011).

    Article  CAS  Google Scholar 

  13. Orme, I. M., Robinson, R. T. & Cooper, A. M. The balance between protective and pathogenic immune responses in the TB-infected lung. Nat. Immunol. 16, 57–63 (2015).

    Article  CAS  Google Scholar 

  14. Kleinnijenhuis, J., Oosting, M., Joosten, L. A., Netea, M. G. & Van, C. R. Innate immune recognition of Mycobacterium tuberculosis. Clin. Dev. Immunol. 2011, 405310 (2015).

    Google Scholar 

  15. Mortaz, E. et al. Interaction of pattern recognition receptors with Mycobacterium tuberculosis. J. Clin. Immunol. 35, 1–10 (2015).

    Article  CAS  Google Scholar 

  16. Stamm, C. E., Collins, A. C. & Shiloh, M. U. Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunol. Rev. 264, 204–219 (2015).

    Article  Google Scholar 

  17. Brooks, M. N. et al. NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG inhuman macrophages. Cell. Microbiol. 13, 402–418 (2011).

    Article  CAS  Google Scholar 

  18. Coulombe, F. et al. Increased NOD2-mediated recognition of N-glycolylmuramyl dipeptide. J. Exp. Med. 206, 1709–1716 (2009).

    Article  CAS  Google Scholar 

  19. Divangahi, M. et al. NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. J. Immunol. 181, 7157–7165 (2008).

    Article  CAS  Google Scholar 

  20. Mishra, B. B. et al. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cell. Microbiol. 12, 1046–1063 (2010).

    Article  CAS  Google Scholar 

  21. Watson, R. O. et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 17, 811–819 (2015).

    Article  CAS  Google Scholar 

  22. Manzanillo, P. S., Shiloh, M. U., Portnoy, D. A. & Cox, J. S. Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages. Cell Host Microbe 11, 469–480 (2012).

    Article  CAS  Google Scholar 

  23. Pathak, S. K. et al. Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat. Immunol. 8, 610–618 (2007).

    Article  CAS  Google Scholar 

  24. Wang, J. et al. Mycobacterium tuberculosis suppresses innate immunity by coopting the host ubiquitin system. Nat. Immunol. 16, 237–245 (2015).

    Article  CAS  Google Scholar 

  25. Wang, L. et al. Mycobacterium tuberculosis lipoprotein MPT83 induces apoptosis of infected macrophages by activating the TLR2/p38/COX-2 signaling pathway. J. Immunol. 198, 4772–4780 (2017).

    Article  CAS  Google Scholar 

  26. Ajibade, A. A., Wang, H. Y. & Wang, R. F. Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 34, 307–316 (2013).

    Article  CAS  Google Scholar 

  27. Ninomiya-tsuji, J. et al. The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252–256 (1999).

    Article  CAS  Google Scholar 

  28. Kanayama, A. et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Mol. Cell 15, 535–548 (2004).

    Article  CAS  Google Scholar 

  29. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

    Article  CAS  Google Scholar 

  30. Scholz, R. et al. Autoactivation of transforming growth factor β-activated kinase 1 is a sequential bimolecular process. J. Biol. Chem. 285, 25753–25766 (2010).

    Article  CAS  Google Scholar 

  31. Mills, K. H. G. Tlr-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11, 807–822 (2011).

    Article  CAS  Google Scholar 

  32. Zheng, R. et al. Notch4 negatively regulates the inflammatory response to Mycobacterium tuberculosis infection by inhibiting TAK1 activation. J. Infect. Dis. 218, 312–323 (2018).

    Article  CAS  Google Scholar 

  33. Wiker, H. G. et al. Cloning, expression and significance of MPT53 for identification of secreted proteins of Mycobacterium tuberculosis. Microb. Pathog. 26, 207–219 (1999).

    Article  CAS  Google Scholar 

  34. Liu, F. et al. MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy. Nat. Comm. 9, 4295 (2018).

    Article  Google Scholar 

  35. Chen, Z. J. Ubiquitination in signaling to and activation of IKK. Immunol. Rev. 246, 95–106 (2012).

    Article  Google Scholar 

  36. Xia, Z.-P. et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461, 114–119 (2009).

    Article  CAS  Google Scholar 

  37. Sakurai, H., Miyoshi, H., Mizukami, J. & Sugita, T. Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1. FEBS Lett. 474, 141–145 (2000).

    Article  CAS  Google Scholar 

  38. Sakurai, H. Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol. 33, 522–530 (2012).

    Article  CAS  Google Scholar 

  39. Jones, C. L. Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues. Bioorg. Med. Chem. 23, 6993–6999 (2015).

    Article  Google Scholar 

  40. Goulding, C. W. et al. Gram-positive DsbE proteins function differently from Gram-negative DsbE homologs. A structure tofunction analysis of DsbE from Mycobacterium tuberculosis. J. Biol. Chem. 279, 3516–3524 (2004).

    Article  CAS  Google Scholar 

  41. Sorrentino, A. et al. The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199–1207 (2008).

    Article  CAS  Google Scholar 

  42. Sweeney, K. A. et al. A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nat. Med. 17, 1261–1268 (2011).

    Article  CAS  Google Scholar 

  43. Abdallah, A. M. et al. Type VII secretion—mycobacteria show the way. Nat. Rev. Microbiol. 5, 883–891 (2007).

    Article  CAS  Google Scholar 

  44. North, R. J. & Jung, Y. J. Immunity to tuberculosis. Ann. Rev. Immunol. 22, 599–623 (2004).

    Article  CAS  Google Scholar 

  45. Dorhoi, A. et al. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J. Clin. Invest. 123, 4836–4848 (2013).

    Article  CAS  Google Scholar 

  46. Ladel, C. H. et al. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect. Immun. 65, 4843–4849 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    Article  CAS  Google Scholar 

  48. Nandi, B. & Behar, S. M. Regulation of neutrophils by interferon-γ limits lung inflammation during tuberculosis infection. J. Exp. Med. 208, 2251–2262 (2011).

    Article  CAS  Google Scholar 

  49. Dallenga, T. & Schaible, U. E. Neutrophils in tuberculosis—defence or booster of disease and targets for host directed therapy? Pathog. Dis. 74, ftw012 (2016).

    Article  Google Scholar 

  50. Paquette, N. et al. Serine/threonine acetylation of TGFβ-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling. Proc. Natl Acad Sci. USA 109, 12710–12715 (2012).

    Article  CAS  Google Scholar 

  51. Chim, N. et al. An extracellular disulfide bond forming protein (DsbF) from Mycobacterium tuberculosis: structural, biochemical, and gene expression analysis. J. Mol. Biol. 396, 1211–1226 (2010).

    Article  CAS  Google Scholar 

  52. Ahsan, M. J. Recent advances in the development of vaccines for tuberculosis. Ther. Adv. Vaccines 3, 66–75 (2015).

    Article  CAS  Google Scholar 

  53. Yuk, J. M. & Jo, E. K. Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis. Clin. Exp. Vaccine Res. 3, 155–167 (2014).

    Article  CAS  Google Scholar 

  54. Yan, D., Wang, X., Luo, L., Cao, X. & Ge, B. Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs. Nat. Immunol. 13, 1063–1071 (2012).

    Article  CAS  Google Scholar 

  55. Bardarov, S. et al. Specialized transduction: an efficient method for generating marked and unmarked targeted gene disruptions in Mycobacterium tuberculosis, M. bovis BCG and M. smegmatis. Microbiology 148, 3007–3017 (2002).

    Article  CAS  Google Scholar 

  56. Liu, H. H. et al. Essential role of TAK1 in thymocyte development and activation. Proc. Natl Acad. Sci. USA 103, 11677–11682 (2006).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Author notes

  1. These authors contributed equally: Lin Wang, Zhonghua Liu.

Authors and Affiliations

  1. Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Lin Wang, Zhonghua Liu, Jie Wang, Haipeng Liu, Juehui Wu, Tianqi Tang, Haohao Li, Hua Yang, Lianhua Qin, Dapeng Ma, Jianxia Chen, Feng Liu, Peng Wang, Ruijuan Zheng, Zhenling Cui, Xiangyang Wu, Xiaochen Huang, Haijiao Liang & Baoxue Ge

  2. Clinical Translation Research Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Haipeng Liu, Dapeng Ma, Jianxia Chen & Baoxue Ge

  3. Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai, China

    Juehui Wu, Tianqi Tang, Haohao Li, Peng Wang, Peng Song, Yilong Zhou, Xiangyang Wu, Haijiao Liang, Shanshan Zhang, Jingjing Cao & Baoxue Ge

  4. Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Chunyan Wu

  5. State Key Lab of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Yiping Chen & Dan Su

  6. Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China

    Xinchun Chen

  7. Department of Microbiology, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Gucheng Zeng

Authors
  1. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhonghua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haipeng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juehui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tianqi Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haohao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lianhua Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dapeng Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jianxia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Feng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ruijuan Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Peng Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yilong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Zhenling Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xiangyang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Xiaochen Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Haijiao Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Shanshan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jingjing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Chunyan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Yiping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Dan Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Xinchun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Gucheng Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Baoxue Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Baoxue Ge.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2, and Supplementary Figures 1–7.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-019-0436-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing