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The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival

Author

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  • Prakruti R. Singh

    (Indian Institute of Science (IISc)
    Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR))

  • Venkatareddy Dadireddy

    (Indian Institute of Science)

  • Shubha Udupa

    (Indian Institute of Science (IISc))

  • Shashwath Malli Kalladi

    (Indian Institute of Science (IISc))

  • Somnath Shee

    (Indian Institute of Science (IISc))

  • Sanjeev Khosla

    (Council of Scientific and Industrial Research-Institute of Microbial Technology, Chandigarh (CSIR -IMTech))

  • Raju S. Rajmani

    (Indian Institute of Science (IISc))

  • Amit Singh

    (Indian Institute of Science (IISc))

  • Suryanarayanarao Ramakumar

    (Indian Institute of Science)

  • Valakunja Nagaraja

    (Indian Institute of Science (IISc)
    Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR))

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.

Suggested Citation

  • Prakruti R. Singh & Venkatareddy Dadireddy & Shubha Udupa & Shashwath Malli Kalladi & Somnath Shee & Sanjeev Khosla & Raju S. Rajmani & Amit Singh & Suryanarayanarao Ramakumar & Valakunja Nagaraja, 2023. "The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43940-6
    DOI: 10.1038/s41467-023-43940-6
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    References listed on IDEAS

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    1. Imtiyaz Yaseen & Prabhjot Kaur & Vinay Kumar Nandicoori & Sanjeev Khosla, 2015. "Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
    2. Qiyao Chai & Xudong Wang & Lihua Qiang & Yong Zhang & Pupu Ge & Zhe Lu & Yanzhao Zhong & Bingxi Li & Jing Wang & Lingqiang Zhang & Dawang Zhou & Wei Li & Wenzhu Dong & Yu Pang & George Fu Gao & Cui Hu, 2019. "A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    3. Pavol Skubák & Navraj S. Pannu, 2013. "Automatic protein structure solution from weak X-ray data," Nature Communications, Nature, vol. 4(1), pages 1-6, December.
    4. Tuhin Bhowmick & Soumitra Ghosh & Karuna Dixit & Varsha Ganesan & Udupi A. Ramagopal & Debayan Dey & Siddhartha P. Sarma & Suryanarayanarao Ramakumar & Valakunja Nagaraja, 2014. "Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
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