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MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection

Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lip...

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Autores principales: Holla, Sahana, Prakhar, Praveen, Singh, Vikas, Karnam, Anupama, Mukherjee, Tanushree, Mahadik, Kasturi, Parikh, Pankti, Singh, Amit, Rajmani, R. S., Ramachandra, Subbaraya G., Balaji, Kithiganahalli Narayanaswamy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988650/
https://www.ncbi.nlm.nih.gov/pubmed/27532872
http://dx.doi.org/10.1371/journal.ppat.1005814
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author Holla, Sahana
Prakhar, Praveen
Singh, Vikas
Karnam, Anupama
Mukherjee, Tanushree
Mahadik, Kasturi
Parikh, Pankti
Singh, Amit
Rajmani, R. S.
Ramachandra, Subbaraya G.
Balaji, Kithiganahalli Narayanaswamy
author_facet Holla, Sahana
Prakhar, Praveen
Singh, Vikas
Karnam, Anupama
Mukherjee, Tanushree
Mahadik, Kasturi
Parikh, Pankti
Singh, Amit
Rajmani, R. S.
Ramachandra, Subbaraya G.
Balaji, Kithiganahalli Narayanaswamy
author_sort Holla, Sahana
collection PubMed
description Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M. tuberculosis H37Rv-, MDR-JAL2287-, H37Ra- and M. bovis BCG-induced genes essential for FM generation in a TLR2-dependent manner. Further, NOTCH1-responsive RNA-binding protein MUSASHI (MSI), targets a transcriptional repressor of JMJD3, Msx2-interacting nuclear target protein, to positively regulate infection-induced JMJD3 expression, FM generation and M2 phenotype. Investigations in in vivo murine models further substantiated these observations. Together, our study has attributed novel roles for JMJD3 and its regulators during mycobacterial infection that assist FM generation and fine-tune associated host immunity.
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spelling pubmed-49886502016-08-29 MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection Holla, Sahana Prakhar, Praveen Singh, Vikas Karnam, Anupama Mukherjee, Tanushree Mahadik, Kasturi Parikh, Pankti Singh, Amit Rajmani, R. S. Ramachandra, Subbaraya G. Balaji, Kithiganahalli Narayanaswamy PLoS Pathog Research Article Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M. tuberculosis H37Rv-, MDR-JAL2287-, H37Ra- and M. bovis BCG-induced genes essential for FM generation in a TLR2-dependent manner. Further, NOTCH1-responsive RNA-binding protein MUSASHI (MSI), targets a transcriptional repressor of JMJD3, Msx2-interacting nuclear target protein, to positively regulate infection-induced JMJD3 expression, FM generation and M2 phenotype. Investigations in in vivo murine models further substantiated these observations. Together, our study has attributed novel roles for JMJD3 and its regulators during mycobacterial infection that assist FM generation and fine-tune associated host immunity. Public Library of Science 2016-08-17 /pmc/articles/PMC4988650/ /pubmed/27532872 http://dx.doi.org/10.1371/journal.ppat.1005814 Text en © 2016 Holla et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Holla, Sahana
Prakhar, Praveen
Singh, Vikas
Karnam, Anupama
Mukherjee, Tanushree
Mahadik, Kasturi
Parikh, Pankti
Singh, Amit
Rajmani, R. S.
Ramachandra, Subbaraya G.
Balaji, Kithiganahalli Narayanaswamy
MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection
title MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection
title_full MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection
title_fullStr MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection
title_full_unstemmed MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection
title_short MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection
title_sort musashi-mediated expression of jmjd3, a h3k27me3 demethylase, is involved in foamy macrophage generation during mycobacterial infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988650/
https://www.ncbi.nlm.nih.gov/pubmed/27532872
http://dx.doi.org/10.1371/journal.ppat.1005814
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