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Histone Methyltransferase SET8 Epigenetically Reprograms Host Immune Responses to Assist Mycobacterial Survival

Singh, Vikas and Prakhar, Praveen and Rajmani, R S and Mahadik, Kasturi and Borbora, Salik Miskat and Balaji, Kithiganahalli Narayanaswamy (2017) Histone Methyltransferase SET8 Epigenetically Reprograms Host Immune Responses to Assist Mycobacterial Survival. In: JOURNAL OF INFECTIOUS DISEASES, 216 (4). pp. 477-488.

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Official URL: http://doi.org/10.1093/infdis/jix322

Abstract

NQO1 and TRXR1 are important host reductases implicated in the regulation of inflammation and apoptosis. Although the transcriptional machinery governing these processes have been extensively investigated, the associated epigenetic regulatory events remain unclear. Here, we report that SET8, a histone H4 lysine 20 monomethylase (H4K20me1), is highly induced during Mycobacterium tuberculosis infection that orchestrates immune evasion strategies through the induction of NQO1 and TRXR1 in vivo. SET8, along with FoxO3a, mediates an active NQO1-PGC1-a complex, which promotes the anti-inflammatory M2 macrophage phenotype, and assists TRXR1-regulated arrest of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Strikingly, the loss-of-function analysis in an in vivo mouse tuberculosis model further corroborated the pivotal role of SET8-responsive NQO1 and TRXR1 in mycobacterial survival. Thus, augmenting host immune responses against Mycobacterium tuberculosis by harnessing the SET8-NQO1/TRXR1 axis with its specific and potent inhibitors could lead to promising host-directed therapeutic adjuvants for tuberculosis treatment.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the OXFORD UNIV PRESS INC, JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 30 Sep 2017 09:18
Last Modified: 30 Sep 2017 09:18
URI: http://eprints.iisc.ac.in/id/eprint/57944

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