Major Histocompatibility Class II Transactivator (CIITA) Mediates Repression of Collagen (COL1A2) Transcription by Interferon γ (IFN-γ)

Xu, Yong; Wang, Lin; Butticè, Giovanna; Sengupta, Pritam K.; Smith, Barbara D.

doi:10.1074/jbc.m404174200

Cited by 55 publications

(93 citation statements)

References 92 publications

(104 reference statements)

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“…Real-time PCR reactions were performed on an ABI-Prism 7700 sequence detection PCR machine (Applied Biosystems, Foster City, CA) according to the manufacturer's protocol. The oligonucleotide forward and reverse PCR primers and fluorescent probes are described in previous studies (22,23,31).…”

Section: Methodsmentioning

confidence: 99%

“…The streptavidin beads (Promega, Madison, WI) were washed three times with ice-cold phosphate-buffered saline supplemented with 1 mM phenylmethylsulfonyl fluoride. Nuclear proteins (100 -200 g) were pre-cleared by incubating with the washed beads for 30 min at 4°C on a shaking platform as described previously (23). Pre-cleared nuclear proteins were prepared by capturing the beads on a magnetic stand and removing the supernatant.…”

Section: Methodsmentioning

confidence: 99%

“…Yet, CIITA is largely responsible for the IFN-␥-induced repression of collagen transcription, because IFN-␥ treatment stimulates CIITA expression, nuclear localization, and occupation on the collagen start site (23). Most importantly, silencing CIITA blocks IFN-␥-induced collagen repression (23).…”

Section: Ppar␥ Co-immunoprecipitates With Rfx5 and Ciita Iv-mentioning

confidence: 99%

“…We have demonstrated that interferon-␥ (IFN-␥), an important inflammatory cytokine, represses collagen transcription, in part, through the induction of regulatory factor for X box 5 (RFX5) complex proteins and Class II transactivator (CIITA), and their recruitment to the collagen transcription start site (22)(23)(24). RFX5 and CIITA are important activators of the immune response through transcriptional activation of major histocompatibility complex II (MHC II).…”

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confidence: 99%

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Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

Farmer

Smith

2007

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Ppar␥ Co-immunoprecipitates With Rfx5 and Ciita Iv-mentioning

confidence: 99%

mentioning

confidence: 99%

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Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

Farmer

Smith

2007

Journal of Biological Chemistry

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“…Loss of functionality because of an inherited deletion within the CIITA gene results in a failure to express MHC class II genes and subsequently present Ags on the surface of APCs, leading to a familial fatal SCID syndrome, bare lymphocyte syndrome (9)(10)(11)(12)(13)(14). In addition to controlling the expression of MHC class II genes, CIITA also plays a role in inducing the expression of other immune system genes including MHC class I molecules (15,16), signaling factors such as IL-4, IL-10, and Fas ligand (17)(18)(19), and a diverse array of .60 other immunologically significant genes (20)(21)(22)(23)(24)(25)(26). Collectively, these observations have clearly established CIITA as a master regulator of Ag presentation and therefore the broad initiation of an acquired immune response.…”

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confidence: 92%

Identification of a Nuclear Export Sequence in the MHC CIITA

Chiu

Gold

Fettig

et al. 2015

The Journal of Immunology

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Initiation of an immune response through expression of MHC class II and related genes is under the control of the CIITA. Normally found in both the cytoplasm and nucleus, CIITA is tightly controlled by a variety of posttranslational modifications as well as interactions with other nuclear and cytoplasmic factors, whereas disruption of this dual subcellular localization impairs CIITA functioning and expression of target genes. Although CIITA has well-defined domains necessary for its nuclear import, the region responsible for the translocation of CIITA from the nucleus has not been characterized. In this study, we identify a leucine-rich motif at residues 717–724 that bears strong homology to known nuclear export sequence (NES) domains. Mutation of this region renders CIITA insensitive to treatment with leptomycin B, an inhibitor of nuclear export, whereas fusion of this domain to a heterologous GFP is sufficient to induce its export to the cytoplasm or cause its retention in the nucleus following leptomycin B treatment. Point mutations of specific leucine residues within the NES disrupt the normal subcellular distribution of the full-length CIITA, impair its ability to interact with the nuclear export factor CRM1, and enhance CIITA-induced gene expression from an MHC class II gene promoter. IFN-γ stimulation of class II genes is further enhanced by inhibiting the nuclear export of endogenous CIITA. Collectively, these data demonstrate the first identification of a specific NES within CIITA and place it among the other protein domains that contribute to the posttranslational regulation of CIITA activity.

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Adenosine signaling inhibits CIITA‐mediated MHC class II transactivation in lung fibroblast cells

Fang

Xia

et al. 2013

Eur J Immunol

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Keywords: Adenosine A2b signaling r CIITA r Epigenetics r MHC class II r Transcriptional regulation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAntigen-restricted activation of T lymphocytes, which are designed to eliminate intracellular pathogens, plays a critical role in adapCorrespondence: Dr. Yong Xu e-mail: yxu2005@gmail.com tive immunity [1]. By their expression of major histocompatibility complex (MHC) molecules, two groups of cells are specialized in presenting processed antigen to T cells: professional antigen presenting cells (p-APCs), which include B cells, dendritic cells, * These authors contributed equally to this work. . Efficient antigen presentation serves several critical pathobiological purposes. One of them is to combat the invasion of opportunistic microbes. Indeed, defective expression of MHC II molecules in fibroblast cells is associated with increased incidence of bacterial and viral infection [5]. Another example whereby the MHC II-dependent immune response plays a predominant role in host defense is the recognition and killing of cancer cells that express foreign epitopes. Mounting evidence has suggested that malignant cells employ a range of strategies to manipulate MHC II expression by fibroblast cells to facilitate evasion [6,7].Adenosine signaling is one of the biologically conserved pathways in mammals that regulates a range of life activities [8]. Recent investigations, however, reveal that adenosine signaling promotes carcinogenesis [9] and infectious diseases [10], indicating that it may target CIITA-mediated MHC II transactivation. Here, we report that adenosine signaling through the A2b receptor downregulates MHC II expression in lung fibroblast cells by repressing CIITA transcription via type III and IV promoters. Our data provide a novel rationale for the blockade of A2b adenosine signaling in the treatment of cancer and infectious disease. Results Adenosine signaling represses MHC II transcriptionWe have previously shown that MHC II expression is inducible by IFN-γ in lung fibroblast cells (IMR-90) in a CIITA-dependent manner [11]. To determine whether adenosine signaling could suppress MHC II expression, we treated IMR-90 cells with an adenosine receptor agonist adenosine-5 N-ethylcarboxamide (NECA). NECA downregulated the induction of HLA-DRα by IFN-γ at both mRNA (Fig. 1A) and protein (Fig. 1B) levels in a dose-response fashion. To examine whether the repression of MHC II expression by NECA took place at the transcription level, an HLA-DR-α promoter-reporter fusion construct was transfected into IMR-90 cells. As shown in Figure 1C, IFN-γ activated the promoter activity but NECA dampened the activation. Similar observations were made in primary mouse lung fibroblast cells (Supporting Information Fig. 1A and B). Therefore, activation of adenosine signaling in lung fibroblast cells is associated with attenuated MHC II transactivation by IFN-γ. Adenosine signaling represses CIITA expression via ...

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Major Histocompatibility Class II Transactivator (CIITA) Mediates Repression of Collagen (COL1A2) Transcription by Interferon γ (IFN-γ)

Cited by 55 publications

References 92 publications

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

Identification of a Nuclear Export Sequence in the MHC CIITA

Adenosine signaling inhibits CIITA‐mediated MHC class II transactivation in lung fibroblast cells

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