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Mycobacterium tuberculosis effector proteins: functional multiplicity and regulatory diversity

Cellular & Molecular Immunology volume 18, pages 1343–1344 (2021)Cite this article

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Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from a single infectious agent. Moreover, TB is responsible for approximately one-quarter of all deaths related to antimicrobial resistance upon the emergence of drug-resistant TB.1 Mtb infection is also associated with multiple other human diseases, such as lung cancer, autoimmune diseases, and metabolic syndromes. Because Mtb lacks classical bacterial toxins (including endotoxins and exotoxins), its pathogenesis mainly involves intricate pathogen-host interplay, which is mediated by a variety of pathogenic factors, including surface-associated and secreted effector proteins. Therefore, a better understanding of the molecular details of the Mtb–host interaction is invaluable for the development of new therapeutic strategies against TB.

Among numerous Mtb effector proteins, mammalian cell entry (Mce) family proteins have been implicated in manipulating multiple host cell signaling pathways.2 For example, Mce3C was identified as an Mtb surface protein that interacts with β2 integrin to trigger SFK-Syk-Vav-Rho-ROCK cascade signaling, leading to enhanced pathogen invasion of macrophages.3 Another study reported that Mce3E, through its DEF motif, suppresses the host ERK1/2 signaling pathway, leading to innate immune suppression and increased pathogen intracellular survival.4 Interestingly, a more recent study by Qiang and colleagues revealed that Mce2E exerts dual host-regulatory functions, including suppressing macrophage innate immune responses and promoting epithelial cell proliferation in a niche-dependent manner.5 As shown in this study, the dual functions of Mce2E depend upon its different domains. On the one hand, Mce2E inhibits ERK and JNK signaling activation by binding to ERK2 and JNK1 via its noncanonical D motif, which is different than classical MAPK-docking motifs and the DEF motif in the Mce3E protein. On the other hand, by binding to host eEF1A1 (eukaryotic translation elongation factor 1A1) via its β-strand region in epithelial cells, Mce2E inhibits the K48-linked polyubiquitination-mediated proteasomal degradation of the eEF1A1 protein to promote tumor cell proliferation and tumor growth in vivo. Thus, through different domains, Mce2E regulates host innate immune responses and carcinogenesis in a cell-specific manner.

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Acknowledgements

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000), the National Natural Science Foundation of China (81825014 and 31830003), the National Key Research and Development Program of China (2017YFA0505900), and the National Science and Technology Major Project (2018ZX10101004).

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  1. Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China

    Lihua Qiang, Yong Zhang & Cui Hua Liu

  2. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China

    Lihua Qiang & Cui Hua Liu

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  1. Lihua Qiang
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Correspondence to Cui Hua Liu.

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Qiang, L., Zhang, Y. & Liu, C.H. Mycobacterium tuberculosis effector proteins: functional multiplicity and regulatory diversity. Cell Mol Immunol 18, 1343–1344 (2021). https://doi.org/10.1038/s41423-021-00676-x

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