MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Zhao, Mojun; Flynt, Frederick L.; Hong, Min Ki; Chen, Han; Gilbert, Carolyn A.; Briley, Nicole T; Bolick, Sophia C.E.; Wright, Kenneth L.; Piskurich, Janet F.

doi:10.1016/j.molimm.2007.01.009

Cited by 34 publications

(39 citation statements)

References 49 publications

(82 reference statements)

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“…Previous studies have shown that both IFN-γ and IL-4 can directly or indirectly target different CIITA promoters to regulate MHC II transcription [10], [44], [45], [46], [47]. Given the modulation of CIITA expression by LANA, we performed luciferase reporter assays by using CIITA promoter pIII and pIV reporter in the presence or absence of LANA in both DG75 and HEK-293 cells followed by treatment with IL-4 or IFN-γ.…”

Section: Resultsmentioning

confidence: 99%

IRF-4-Mediated CIITA Transcription Is Blocked by KSHV Encoded LANA to Inhibit MHC II Presentation

et al. 2013

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Peptides presentation to T cells by MHC class II molecules is of importance in initiation of immune response to a pathogen. The level of MHC II expression directly influences T lymphocyte activation and is often targeted by various viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) encoded LANA is known to evade MHC class I peptide processing, however, the effect of LANA on MHC class II remains unclear. Here, we report that LANA down-regulates MHC II expression and presentation by inhibiting the transcription of MHC II transactivator (CIITA) promoter pIII and pIV in a dose-dependent manner. Strikingly, although LANA knockdown efficiently disrupts the inhibition of CIITA transcripts from its pIII and pIV promoter region, the expression of HLA-DQβ but no other MHC II molecules was significantly restored. Moreover, we revealed that the presentation of HLA-DQβ enhanced by LANA knockdown did not help LANA-specific CD4+ T cell recognition of PEL cells, and the inhibition of CIITA by LANA is independent of IL-4 or IFN-γ signaling but dependent on the direct interaction of LANA with IRF-4 (an activator of both the pIII and pIV CIITA promoters). This interaction dramatically blocked the DNA-binding ability of IRF-4 on both pIII and pIV promoters. Thus, our data implies that LANA can evade MHC II presentation and suppress CIITA transcription to provide a unique strategy of KSHV escape from immune surveillance by cytotoxic T cells.

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Section: Resultsmentioning

confidence: 99%

IRF-4-Mediated CIITA Transcription Is Blocked by KSHV Encoded LANA to Inhibit MHC II Presentation

et al. 2013

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“…More recent evidence has shown that the activity of CIITA is tightly regulated at multiple levels, including expression, GTP binding, dimerization, nuclear translocation, and phosphorylation (42,(61)(62)(63)(64)(65), whereas the intracellular signaling pathways involved in CIITA regulation, namely phosphorylation, are only starting to emerge. Although several kinases have been identified as mediators of CIITA expression and function, their respective roles differ, reflecting a complex regulatory mechanism alternatively capable of activating or inhibiting CIITA function.…”

Section: Discussionmentioning

confidence: 99%

Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

Voong

Slater

Kratovac

et al. 2008

Journal of Biological Chemistry

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The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.The class II transactivator CIITA 2 plays a critical role in initiating an immune response by activating the expression of major histocompatibility (MHC) class II genes and associated molecules (2-6). MHC II glycoproteins are necessary for the presentation of antigenic peptides to CD4 ϩ T lymphocytes and the subsequent initiation and propagation of CD4 ϩ T cell-mediated immune responses and are involved in the development and maintenance of homeostasis of the CD4 ϩ T cell population. Although constitutive expression of MHC class II genes is primarily restricted to a specific subset of antigen-presenting cells that include B cells and dendritic cells, expression is inducible in a variety of other cell types and tissues by cytokines such as interferon-␥ and tumor necrosis factor-␣ (1). Both constitutive and inducible expression of MHC II and other related genes are contingent upon the activation of CIITA (7,8). Loss of a functional CIITA protein results in an immunodeficiency called bare lymphocyte syndrome, which is characterized by a complete absence of MHC class II-mediated antigen presentation. Patients with this disease suffer from recurrent infections due to opportunistic infections and, ultimately, death in early childhood (9 -11).CIITA is a protein of 1130 amino acids that does not bind directly to DNA. Instead, it regulates gene expression by interacting with other transcription factors and chromatin-remodeling proteins at the W/X/Y regulatory elements in the promoter regions of class II genes (for review, see Refs. 12-17). Nuclear factors binding to CIITA include the regulatory factor X (RFX) complex (RFX5, RFXAP, RFXANK/RFX-B) (18) and nuc...

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“…CIITA PIII drives constitutive expression of CIITA in B cells and activated T cells. CIITA PIV is a principal IFN-␥-inducible promoter and controls the IFN-␥-inducible expression of CIITA in most MHC class II-negative cells (41). To clarify whether Zta affected CIITA transcription, we first examined the effect of Zta on the CIITA promoter activity.…”

Section: With a Consensus Sequence (T(g/t)(a/ T)g(t/c)(g/c/a)a) At ϫ1287mentioning

confidence: 99%

Down-Regulation of MHC Class II Expression through Inhibition of CIITA Transcription by Lytic Transactivator Zta during Epstein-Barr Virus Reactivation

Li¹,

Lü²,

Chen³

et al. 2009

The Journal of Immunology

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The presentation of peptides to T cells by MHC class II molecules is of critical importance in specific recognition to a pathogen by the immune system. The level of MHC class II directly influences T lymphocyte activation. The aim of this study was to identify the possible mechanisms of the down-regulation of MHC class II expression by Zta during EBV lytic cycle. The data in the present study demonstrated that ectopic expression of Zta can strongly inhibit the constitutive expression of MHC class II and CIITA in Raji cells. The negative effect of Zta on the CIITA promoter activity was also observed. Scrutiny of the DNA sequence of CIITA promoter III revealed the presence of two Zta-response element (ZRE) motifs that have complete homology to ZREs in the DR and left-hand side duplicated sequence promoters of EBV. By chromatin immunoprecipitation assays, the binding of Zta to the ZRE221 in the CIITA promoter was verified. Site-directed mutagenesis of three conserved nucleotides of the ZRE221 substantially disrupted Zta-mediated inhibition of the CIITA promoter activity. Oligonucleotide pull-down assay showed that mutation of the ZRE221 dramatically abolished Zta binding. Analysis of the Zta mutant lacking DNA binding domain revealed that the DNA-binding activity of Zta is required for the trans repression of CIITA. The expression of HLA-DRα and CIITA was restored by Zta gene silencing. The data indicate that Zta may act as an inhibitor of the MHC class II pathway, suppressing CIITA transcription and thus interfering with the expression of MHC class II molecules.

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MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Cited by 34 publications

References 49 publications

IRF-4-Mediated CIITA Transcription Is Blocked by KSHV Encoded LANA to Inhibit MHC II Presentation

IRF-4-Mediated CIITA Transcription Is Blocked by KSHV Encoded LANA to Inhibit MHC II Presentation

Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

Down-Regulation of MHC Class II Expression through Inhibition of CIITA Transcription by Lytic Transactivator Zta during Epstein-Barr Virus Reactivation

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