Mycobacterium tuberculosis EsxL inhibits MHC-II expression by promoting hypermethylation in class-II transactivator loci in macrophages

Sengupta, Srabasti ; Naz, Saba ; Das, Ishani ; Ahad, Abdul ; Padhi, Avinash ; Naik, Sumanta Kumar ; Ganguli, Geetanjali ; Pattanaik, Kali Prasad ; Raghav, Sunil Kumar ; Nandicoori, Vinay Kumar ; Sonawane, Avinash (2017) Mycobacterium tuberculosis EsxL inhibits MHC-II expression by promoting hypermethylation in class-II transactivator loci in macrophages Journal of Biological Chemistry, 292 (17). pp. 6855-6868. ISSN 0021-9258

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Official URL: http://www.jbc.org/content/292/17/6855

Related URL: http://dx.doi.org/10.1074/jbc.M117.775205

Abstract

Mycobacterium tuberculosis (Mtb) is known to modulate the host immune responses to facilitate its persistence inside the host cells. One of the key mechanisms includes repression of class-II transactivator (CIITA) and MHC-II expression in infected macrophages. However, the precise mechanism of CIITA and MHC-II down-regulation is not well studied. Mtb 6-kDa early secretory antigenic target (ESAT-6) is a known potent virulence and antigenic determinant. Mtb genome encodes 23 such ESAT-6 family proteins. We herein report that Mtb and M. bovis-BCG infection down-regulated the expression of CIITA/MHC-II by inducing hypermethylation in histone H3 Lysine 9 (H3K9me2/3). Further, we show that Mtb ESAT-6 family protein EsxL, encoded by Rv1198, is responsible for the down-regulation of CIITA/MHC-II by inducing H3K9me2/3. We further report that Mtb esxL induced the expression of nitric oxide synthetase (iNOS), NO production and p38-MAPK pathway, which in turn was responsible for the increased H3K9me2/3 in CIITA via up-regulation of euchromatic histone-lysine N-methyltransferase 2 (G9a). In contrast, inhibition of iNOS, p38-MAPK and G9a abrogated H3K9me2/3 resulting in increased CIITA expression. Chromatin immune precipitation assay confirmed that hypermethylation at the promoter IV (pIV) region of CIITA is mainly responsible for the CIITA down regulation and subsequently antigen presentation. We found that co-culture of macrophages infected with esxL expressing M. smegmatis and mouse spleenocytes led to down-regulation of IL-2, a key cytokine involved in T-cell proliferation. In summary, we show that Mtb esxL inhibits antigen presentation by enhancing H3K9me2/3 on CIITA promoter thereby repressing its expression through NO and p38-MAPK activation.

Item Type:Article
Source:Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
Keywords:Mycobacterium tuberculosis; EsxL; Nitric Oxide; Histone Trimethylation; CIITA; MHC-II; Macrophages; P38-MAPK Pathway
ID Code:113506
Deposited On:25 May 2018 06:11
Last Modified:25 May 2018 06:11

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