Tongji University School of Medicine



Ge Baoxue’s research team revealed that sulfur-oxidated molecular character of proteins secreted by mycobacterium tuberculosis could be recognized by the host protein kinase and activate immunity to tuberculosis

CreatedTime:2019-05-22 14:31:27 Click:

The Mycobacterium tuberculosis infection remains one of the leading reasons causing human beings to die of infection. According to the World Health Organization(WHO), there were one million and six hundred thousand mortalities of over ten million new cases through out the world in 2017[1]. Previous researches found that various ingredients of mycobacterium tuberculosis (Mtb) could be recognized by the pattern recognition receptor of innate immune cells in host and activate the downstream inflammatory immune responses. Mycobacterium tuberculosis are able to use many sorts of secretion system to make large amounts of proteins pass through the hydrophobic bacteria wall structure and be secreted out, while whether these secreted proteins will be recognized or not and the specific recognition mechanism are not clear yet.


On May 21, 2019, Ge Baoxue’s research team from Shanghai Pulmonary Hospital affiliated to Tongji University published the article named Oxidization of TGFβ-activated kinase by MPT53 is required for immunity to Mycobacterium tuberculosis in Nature Microbiologwhich revealed that Mycobacterium tuberculosis secretory proteins MPT53 (Rv2878c) can directly combine with the host signal molecules TAK1 (TGF -β- activated kinase 1) and facilitate TAK1 to build disulfide bond formation with its sulfur oxido-rdeuctase activity, so as to promote the interaction between TRAFs and TAB1 molecular with TAK1 and therefore activate TAK1 and the downstream inflammatory pathways. This research provide new ideas for the host signal molecular perception of mycobacterium tuberculosis infection and become theoretical support of the future tuberculosis vaccine development.


To explore the influence of mycobacterium tuberculosis secretory proteins to the innate immune signaling pathways in host, they screened more than 200 secretory proteins and lipoproteins of tuberculosis bacterium by function with HEK293T cells luciferase reporter gene system, and the results showed that secretory protein MPT53 can significantly activate the NF-κB and AP-1 inflammatory signal paths. At the same time, the activity of MAPKs and NF-κB signaling pathways activated by bacterium tuberculosis were found declined in both macrophages and lung tissues of mice with H37Rv infection after knocking out MPT53, and the level of inflammatory factor also become lower.


Presently the inflammatory factors induced by mycobacterium tuberculosis are known to be produced mainly by TLR signal paths [2, 3].Researchers’ further study revealed that MPT53 has interaction with the key signal molecular TAK1 protein kinase in TLR signal pathway. Researchers found that the existence of MPT53 can significantly increase the TAK1 kinase activity in both HEK293T cell overexpression system and macrophage infection model. Through analyzing the structure and comparing sequence, MPT53 protein has typical sulfur oxidation-reduction function area, and after mutating the activate site, MPT53 can’t increase TAK1 kinase activity and activate downstream inflammatory signal pathways. Further research showed that MPT53 could oxidize C210 of TAK1, causing it to form disulfide bond and facilitating TRAFs and TAB1 to form activated complex with TAK1.At last, researchers built the recombinant Mycobacterium Smegmatis which overexpresses MPT53 (Ms-MPT53), they found that Ms-MPT53 could protect the host from the pathological damage of lung tissue caused by mycobacterium tuberculosis and reduce the Bacterium load of the lung.


The recognition of mycobacterium tuberculosis is the key step for host to start immune response, while mycobacterium tuberculosis could secrete a large number of proteins to the outside of the bacteria [4], and now we all think that most secretory proteins can inhibit the innate immune response of host and promote the pathogenicity of mycobacterium tuberculosis infection, which help mycobacterium tuberculosis achieve the goal of immune escape. But the study found that the molecular characteristics of sulfur oxidation reduction function area in secretory proteins MPT53 could be recognized by the host TAK1 protein kinase and activate one inflammatory immune response pathway that doesn’t rely on receptors, which is the restriction factors of the disease morbidity of mycobacterium tuberculosis infection, and it also to provides more theoretical basis for the function of mycobacterium tuberculosis secretory proteins.


It’s reported that Doctor Wang Lin and assistant researcher Liu Zhonghua, from Shanghai Pulmonary Hospital affiliated to Tongji University, are co-first author of this paper. And professor Ge Baoxue, from TUSM and Shanghai Pulmonary Hospital affiliated to Tongji University, is the corresponding author. Professor Ge Baoxue is Director of Shanghai Key Lab of Tuberculosis which is approved to establish by the Shanghai Committee of Science and Technology in 2004, focuses on basic and clinical translational research of tuberculosis prevention, diagnosis and therapy, relies on Shanghai Pulmonary Hospital affiliated to Tongji University. This research attained strong supports of Prof. Chen Zhijian from the Southwestern Medical Center of Texas University, Doctor Lv liangDong from Fudan University and researcher Mi KaiXia from the Key Laboratory of Pathogenic Microorganisms and Immunology of Chinese Academy of Science.





[1] World Health Organization. WHO Global Tuberculosis Report 2018 (WHO, 2018).

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

[3] 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).

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


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