IFN Regulatory Factor-2 Cooperates with STAT1 to Regulate Transporter Associated with Antigen Processing-1 Promoter Activity

Rouyez, M C; Lestingi, Marta; Charon, M; Fichelson, Serge; Buzyn, Agnès; Dusanter‐Fourt, Isabelle

doi:10.4049/jimmunol.174.7.3948

Cited by 54 publications

(37 citation statements)

References 56 publications

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“…6A). IFN-␥ treatment led to the transcription activation of TAP1, PSMB9, and PARL, which is consistent with previously published studies (48). Ectopic expression of LANA inhibited the IFN-␥-inducible transcription of TAP1, PSMB9, and PARL by ca.…”

Section: Resultssupporting

confidence: 92%

Identification of Host-Chromosome Binding Sites and Candidate Gene Targets for Kaposi's Sarcoma-Associated Herpesvirus LANA

Lü

Tsai

Chen

et al. 2012

J Virol

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LANA is essential for tethering the Kaposi's sarcoma-associated herpesvirus (KSHV) genome to metaphase chromosomes and for modulating host-cell gene expression, but the binding sites in the host-chromosome remain unknown. Here, we use LANA-specific chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) to identify LANA binding sites in the viral and host-cell genomes of a latently infected pleural effusion lymphoma cell line BCBL1. LANA bound with high occupancy to the KSHV genome terminal repeats (TR) and to a few minor binding sites in the KSHV genome, including the LANA promoter region. We identified 256 putative LANA binding site peaks with P < 0.01 and overlap in two independent ChIP-Seq experiments. We validated several of the high-occupancy binding sites by conventional ChIP assays and quantitative PCR. Candidate cellular LANA binding motifs were identified and assayed for binding to purified recombinant LANA protein in vitro but bound with low affinity compared to the viral TR binding site. More than half of the LANA binding sites (170/256) could be mapped to within 2.5 kb of a cellular gene transcript. Pathways and Gene Ontogeny (GO) analysis revealed that LANA binds to genes within the p53 and tumor necrosis factor (TNF) regulatory network. Further analysis revealed partial overlap of LANA and STAT1 binding sites in several gamma interferon (IFN-γ)-regulated genes. We show that ectopic expression of LANA can downmodulate IFN-γ-mediated activation of a subset of genes, including the TAP1 peptide transporter and proteasome subunit beta type 9 (PSMB9), both of which are required for class I antigen presentation. Our data provide a potential mechanism through which LANA may regulate several host cell pathways by direct binding to gene regulatory elements.

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Section: Resultssupporting

confidence: 92%

Identification of Host-Chromosome Binding Sites and Candidate Gene Targets for Kaposi's Sarcoma-Associated Herpesvirus LANA

Lü

Tsai

Chen

et al. 2012

J Virol

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“…The high basal levels of TAP1 and LMP2 mRNA in H929 is consistent with constitutive expression of IRF-1 and IRF-2, as both IRFs have been shown to contribute to regulation of the bidirectional promoter (41,42). This contrasts with the low levels of CIITA-pIV mRNA.…”

Section: Ifn-␥-mediated Induction Of Ciita-piv Is Repressed In the Mysupporting

confidence: 61%

Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

Tooze

Stephenson

Doody

2006

The Journal of Immunology

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MHC class II is expressed in restricted lineages and is modulated in response to pathogens and inflammatory stimuli. This expression is controlled by MHC CIITA, which is transcribed from multiple promoters. Although factors required for induction of CIITA are well characterized, less is known about the mechanisms leading to repression of this gene. During plasma cell differentiation, B lymphocyte-induced maturation protein-1 (PRDM1/Blimp-1) represses promoter (p)III of CIITA, responsible for constitutive expression in B cells. pIV is inducible by IFN-γ in epithelia, macrophages and B cells. An IFN regulatory factor-element (IRF-E) in CIITA-pIV, which is bound by IRF-1 and IRF-2, is necessary for this response. This site matches the PRDM1/Blimp-1 consensus binding site, and PRDM1/Blimp-1 is expressed in cell lineages in which this promoter is operative. We, therefore, investigated whether PRDM1 regulates CIITA-pIV and found that PRDM1 bound to CIITA-pIV in vivo and the IRF-E in vitro. PRDM1 repressed IFN-γ-mediated induction of a CIITA-pIV luciferase reporter in a fashion dependent on an intact consensus sequence and competes with IRF-1/IRF-2 for binding to the IRF-E and promoter activation. In human myeloma cell lines that express IRFs, PRDM1 occupancy of CIITA-pIV was associated with resistance to IFN-γ stimulation, while short interfering RNA knockdown of PRDM1 led to up-regulation of CIITA. Our data indicate that PRDM1 is a repressor of CIITA-pIV, identifying a target of particular relevance to macrophages and epithelia. These findings support a model in which PRDM1/Blimp-1 can modulate the cellular response to IFN-γ by competing with IRF-1/IRF-2 dependent activation of target promoters.

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“…The promoters of these genes have an AAGTGA hexamer nucleotide consensusbinding motif for IRF-2 (23-25, 46, 47), similar to what we found in the promoter of IFNGR1. Our results certainly did not exclude the possibility that IRF-2 bound to this motif by interacting with other regulatory proteins, as have been shown under some conditions (48)(49)(50), because besides the canonical binding sequences, upstream and downstream bases were also used by IRF-2 for its full inhibitory activity. The location of AAGTGA in the IFNGR1 is adjacent to the binding site of the cAMP-responsive element binding protein/CRE-BP1/c-Jun transcription factors, and IRF-2 might hinder these two transcription factors.…”

Section: Discussionmentioning

confidence: 63%

Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

et al. 2008

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IFN-; is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-; receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-; by repressing transcription of IFN-;-induced genes. Thus far, few studies have explored the influences of IFN-; on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-; in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-; was increased in tumor tissues and positively correlated with tumor progression and IRF-2 expression, whereas the level of IFNGR1 was decreased and negatively correlated with tumor progression and IRF-2 expression. Consistently, in vitro experiments showed that low concentration of IFN-; induced the expression of IRF-2 with potential promotion of cell growth, and moreover, IRF-2 was able to suppress IFNGR1 transcription in human esophageal cancer cells by binding a specific motif in IFNGR1 promoter, which lowered the sensitivity of esophageal cancer cells to IFN-;. Taken together, our results disclosed a new IRF-2-mediated inhibitory mechanism for IFN-;-induced pathway in esophageal cancer cells: IFN-; induced IRF-2 upregulation, then up-regulated IRF-2 decreased endogenous IFNGR1 level, and finally, the loss of IFNGR1 turned to enhance the resistance of esophageal cancer cells to IFN-;. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-; and IFNGR1 in human esophageal cancers.

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IFN Regulatory Factor-2 Cooperates with STAT1 to Regulate Transporter Associated with Antigen Processing-1 Promoter Activity

Cited by 54 publications

References 56 publications

Identification of Host-Chromosome Binding Sites and Candidate Gene Targets for Kaposi's Sarcoma-Associated Herpesvirus LANA

Identification of Host-Chromosome Binding Sites and Candidate Gene Targets for Kaposi's Sarcoma-Associated Herpesvirus LANA

Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

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