Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling.
During infection of macrophages, prolonged signaling by Mycobacterium tuberculosis (Mtb) or its 19-kDa lipoprotein (LpqH; Rv3763) inhibits IFN-gamma-induced expression of several immune function genes, including class II transactivator (CIITA), which regulates class II MHC. Mtb does not inhibit early IFN-gamma signaling events, e.g., Stat1alpha activation. This study analyzed downstream mechanisms that regulate the transcription of MHC2TA, the gene encoding CIITA. Chromatin immunoprecipitation showed that IFN-gamma induced acetylation of histones H3 and H4 at the CIITA promoter IV (pIV). In contrast, IFN-gamma-dependent histone acetylation at CIITA pIV was inhibited by Mtb or 19-kDa lipoprotein. Mtb 19-kDa lipoprotein also inhibited IFN-gamma-dependent recruitment of Brahma-related gene 1, a chromatin remodeling protein, to CIITA pIV. Mtb 19-kDa lipoprotein did not inhibit histone acetylation in TLR2(-/-) macrophages. Furthermore, 19-kDa lipoprotein did not inhibit CIITA expression or IFN-gamma-dependent histone acetylation of CIITA pIV in macrophages treated with inhibitors of MAPKs p38 or ERK. Thus, CIITA expression was inhibited by TLR2-induced MAPK signaling that caused histone hypoacetylation at CIITA pIV and suppression of CIITA transcription. Chromatin remodeling at MHC2TA is a novel target of inhibition by Mtb. These mechanisms may diminish class II MHC expression by infected macrophages, contributing to immune evasion by Mtb.
Pennini
Meghan E
ME
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Pai
Rish K
RK
Schultz
David C
DC
Boom
W Henry
WH
Harding
Clifford V
CV
D000107:Acetylation; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection
D001426:Bacterial Proteins; D006657:Histones; D008074:Lipoproteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D015534:Trans-Activators; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases