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.
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Meghan E
ME
Pennini
Rish K
RK
Pai
David C
DC
Schultz
W Henry
WH
Boom
Clifford V
CV
Harding
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