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

Prakruti R. Singh, Venkatareddy Dadireddy, Shubha Udupa, Shashwath Malli Kalladi, Somnath Shee, Sanjeev Khosla, Raju S. Rajmani, Amit Singh, Suryanarayanarao Ramakumar and Valakunja Nagaraja ()
Additional contact information
Prakruti R. Singh: Indian Institute of Science (IISc)
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)

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43940-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43940-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43940-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().