title: MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection.
abstract: 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.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Prakhar
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Karnam
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Mukherjee
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Mahadik
authors.affiliation: Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Pankti
authors.initials: P
authors.lastname: Parikh
authors.affiliation: Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: R S
authors.initials: RS
authors.lastname: Rajmani
authors.affiliation: Central Animal Facility, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Subbaraya G
authors.initials: SG
authors.lastname: Ramachandra
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D006099:Granuloma / Q000276:immunology / Q000382:microbiology; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D056484:Jumonji Domain-Containing Histone Demethylases / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D009164:Mycobacterium Infections / Q000276:immunology* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000276:immunology* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism
chemical_list: C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse