Singh, PR and Dadireddy, V and Udupa, S and Kalladi, SM and Shee, S and Khosla, S and Rajmani, RS and Singh, A and Ramakumar, S and Nagaraja, V (2023) The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival. In: Nature Communications, 14 (1).
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Abstract
Mycobacterium tuberculosis has evolved several mechanisms to counter host defense arsenals for its proliferation. Here we report that M. tuberculosis employs a multi-pronged approach to modify host epigenetic machinery for its survival. It secretes methyltransferase (MTase) Rv2067c into macrophages, trimethylating histone H3K79 in a non-nucleosomal context. Rv2067c downregulates host MTase DOT1L, decreasing DOT1L-mediated nucleosomally added H3K79me3 mark on pro-inflammatory response genes. Consequent inhibition of caspase-8-dependent apoptosis and enhancement of RIPK3-mediated necrosis results in increased pathogenesis. In parallel, Rv2067c enhances the expression of SESTRIN3, NLRC3, and TMTC1, enabling the pathogen to overcome host inflammatory and oxidative responses. We provide the structural basis for differential methylation of H3K79 by Rv2067c and DOT1L. The structures of Rv2067c and DOT1L explain how their action on H3K79 is spatially and temporally separated, enabling Rv2067c to effectively intercept the host epigenetic circuit and downstream signaling. © 2023, The Author(s).
| Item Type: | Journal Article |
|---|---|
| Publication: | Nature Communications |
| Publisher: | Nature Research |
| Additional Information: | The copyright for this article belongs to authors. |
| Keywords: | caspase 8; histone H3; lysine; methyltransferase; monomer; histone; methyltransferase, apoptosis; survival; tuberculosis, amino acid sequence; animal tissue; apoptosis; Article; carboxy terminal sequence; cell death; cell fractionation; chromatin; confocal microscopy; controlled study; crystal structure; cytokine response; cytoplasm; down regulation; enzyme active site; epigenetics; female; gene expression; histopathology; homologous recombination; immunoblotting; immunohistochemistry; immunoprecipitation; Leporidae; macrophage; male; methylation; mouse; Mycobacterium tuberculosis; necrosis; nonhuman; nuclear import; nuclear localization signal; nucleosome; pathogenesis; polyacrylamide gel electrophoresis; survival; tuberculosis; genetic epigenesis; genetics; metabolism, Epigenesis, Genetic; Histones; Methylation; Methyltransferases; Mycobacterium tuberculosis |
| Department/Centre: | Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research Division of Physical & Mathematical Sciences > Physics |
| Date Deposited: | 16 Nov 2024 15:37 |
| Last Modified: | 16 Nov 2024 15:37 |
| URI: | http://eprints.iisc.ac.in/id/eprint/85322 |
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