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Nat Microbiol. 2019 May 20. doi: 10.1038/s41564-019-0436-3. [Epub ahead of print]

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

Wang L1, Liu Z1, Wang J1, Liu H1,2, Wu J1,3, Tang T1,3, Li H1,3, Yang H1, Qin L1, Ma D1,2, Chen J1,2, Liu F1, Wang P1,3, Zheng R1, Song P3, Zhou Y3, Cui Z1, Wu X1,3, Huang X1, Liang H1,3, Zhang S3, Cao J3, Wu C4, Chen Y5, Su D5, Chen X6, Zeng G7, Ge B8,9,10.

Author information

1
Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
2
Clinical Translation Research Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
3
Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai, China.
4
Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
5
State Key Lab of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
6
Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China.
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.
8
Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. baoxue_ge@tongji.edu.cn.
9
Clinical Translation Research Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. baoxue_ge@tongji.edu.cn.
10
Department of Microbiology and Immunology, School of Medicine, Tongji University, Shanghai, China. baoxue_ge@tongji.edu.cn.

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.

PMID:
31110366
DOI:
10.1038/s41564-019-0436-3

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