Affinage

CIITA

MHC class II transactivator · UniProt P33076

Length
1130 aa
Mass
123.4 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIITA is the master transcriptional coactivator of the MHC class II response, sufficient to switch on MHC class II genes in class II-negative cells and acting as the general regulator of both constitutive and IFN-γ-inducible class II expression (PMID:8016643, PMID:7600294). It does not bind DNA itself but is recruited to the conserved S-X-Y promoter module through the RFX complex (RFX5, RFXANK), NF-Y (NF-YB/NF-YC), and CREB, with these LRR-independent protein-protein contacts positioning CIITA at the enhanceosome while its leucine-rich repeats govern nuclear localization and stable promoter occupancy (PMID:11003667, PMID:9806639, PMID:16730065). Once recruited, CIITA orchestrates a coordinated activation program: it directs SWI/SNF-dependent chromatin remodeling via the BRG1 ATPase, recruits the CBP/GCN5 acetyltransferases to drive histone acetylation, and promotes transcription initiation by recruiting CDK7/CDK9 and enhancing Ser5 phosphorylation of RNA Pol II for promoter clearance (PMID:11953317, PMID:14517250, PMID:11889043). Genome-wide it binds hundreds of active promoters and enhancers, including distal S'-Y' modules, where it poises chromatin through H3K27 acetylation (PMID:25753668, PMID:15528357). CIITA expression is itself the principal control point, set by multiple cell-type-specific promoters whose use depends on STAT1/IRF-1 (IFN-γ-inducible promoter IV), PU.1/IRF8 (B-cell and DC promoters), and NFAT5 (myeloid), and is silenced by promoter hypermethylation, EZH2/H3K27me3, and PRDM1-recruited G9a/HDAC2 repression (PMID:9184229, PMID:12052885, PMID:20363966, PMID:30327417, PMID:11053628, PMID:17911618, PMID:21216962). CIITA activity and stability are tuned by post-translational modifications—inhibitory phosphorylation at Ser286/288/293, SIRT1-reversible acetylation controlling nuclear accumulation, PRMT1 methylation driving degradation, and FBXO11-mediated ubiquitin-dependent proteasomal turnover as the major determinant of its half-life (PMID:15210796, PMID:21890893, PMID:28094290, PMID:37279268). Beyond antigen presentation CIITA acts as a viral restriction factor, sequestering the HTLV-1 Tax-1 and HIV-1 Tat transactivators and inducing the CD74 p41 isoform to block cathepsin-dependent entry of Ebola virus and SARS-CoV-2, and it can also act as a context-dependent repressor, recruiting SUV39H1 to silence eNOS and suppressing IL-10 (PMID:21813598, PMID:27089879, PMID:32855215, PMID:30716531, PMID:15661876).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 High

    Established that a single factor controls the MHC class II regulon, answering whether class II induction by IFN-γ required a dedicated master regulator.

    Evidence Transfection of CIITA into class II-negative cells and IFN-γ stimulation, plus genetic complementation of IFN-γ-defective mutant cell lines

    PMID:7600294 PMID:8016643

    Open questions at the time
    • Did not define how CIITA reaches the promoter
    • Mechanism of transactivation unresolved
  2. 1995 High

    Defined the partition of labor between CIITA and the RFX complex, showing both are essential and act on overlapping sets of MHC genes including HLA-DM.

    Evidence cDNA complementation of distinct regulatory mutant cell lines for HLA-DMA/DMB

    PMID:7495736

    Open questions at the time
    • Physical relationship between CIITA and RFX not yet shown
    • Promoter element requirements undefined
  3. 1997 High

    Explained cell-type-specific and inducible class II expression by mapping CIITA to multiple distinct promoters and identifying CIITA-independent regulatory routes.

    Evidence Promoter-specific reporter assays, cell-type expression analysis, and dominant-negative CIITA lacking the activation domain

    PMID:9144488 PMID:9184229

    Open questions at the time
    • Upstream transcription factors at each promoter not identified
    • Basis of CIITA-independent HLA-DQ regulation unknown
  4. 1998 High

    Showed CIITA also governs MHC class I and beta2-microglobulin via the RFX/S-X-Y machinery, and that physiological class II silencing in trophoblast reflects failure to induce CIITA itself.

    Evidence Bare lymphocyte syndrome cell lines lacking RFX5/RFXAP; transfection rescue and exclusion of upstream defects in trophoblast

    PMID:11053628 PMID:9806639 PMID:9894561

    Open questions at the time
    • Cause of CIITA promoter silencing in trophoblast not yet defined
    • Direct CIITA-RFX contact still inferred
  5. 2000 High

    Mapped the structural basis of CIITA recruitment and assembly, distinguishing LRR-dependent localization/promoter binding from LRR-independent partner contacts and self-association.

    Evidence LRR alanine mutagenesis, ChIP, co-IP with RFX5/RFXANK/NF-YB/NF-YC, nuclear localization assays, and homodimerization mapping; bisulfite analysis of promoter IV in trophoblast

    PMID:11003667 PMID:11053628 PMID:11438649

    Open questions at the time
    • Identity of the LRR-sensitive 33 kDa partner unresolved
    • Functional role of GTP-binding domain self-association unclear
  6. 2002 High

    Resolved both how CIITA is induced and what it does at target promoters, defining the STAT1→IRF-1 kinetic cascade, BRG1/SWI/SNF chromatin remodeling, and CDK7/CDK9-mediated Pol II Ser5 phosphorylation.

    Evidence ChIP kinetics with bisulfite sequencing, BRG1 reconstitution with ATPase-dead control, kinase recruitment assays, and ChIP across four MHC-II promoters

    PMID:11889043 PMID:11953317 PMID:12052885 PMID:14517250

    Open questions at the time
    • Whether CIITA enzymatic activities are intrinsic vs recruited not settled
    • Quantitative contributions of each step vary by promoter
  7. 2003 High

    Extended the CIITA regulon beyond MHC to identify functional non-MHC targets relevant to antigen presentation, such as plexin-A1 in dendritic cells.

    Evidence cDNA microarray in CIITA-deficient mouse DCs with shRNA validation and T-cell stimulation assays

    PMID:12910265

    Open questions at the time
    • Promoter elements mediating CIITA control of plexin-A1 undefined
    • Breadth of non-MHC targets not yet genome-wide
  8. 2004 Medium

    Proposed CIITA as a general transcription factor with intrinsic acetyltransferase/kinase activities and TAF1-like function, and uncovered distal S'-Y' enhancers and inhibitory phosphorylation as activity controls.

    Evidence Biochemical activity assays and TAF1 complementation (reviewed); ChIP/reporter of distal enhancers; Ser286/288/293 mutagenesis with fractionation

    PMID:15210796 PMID:15528357 PMID:24391648

    Open questions at the time
    • Primary structural/biochemical evidence for intrinsic enzymatic activities limited
    • Kinase responsible for inhibitory Ser phosphorylation not identified
  9. 2006 Medium

    Defined transcriptional repression of CIITA by pathogens and the cofactor environment, linking TLR2/MAPK signaling, C/EBP, EZH2, ZXDC/ZXDA, and CREB to CIITA promoter control and coactivation.

    Evidence ChIP with TLR2-KO macrophages and MAPK inhibitors; C/EBPβ LIP transfection; EZH2 RNAi; yeast two-hybrid and co-IP for ZXDC/ZXDA; CREB mutant co-IP and ChIP

    PMID:16547269 PMID:16600381 PMID:16730065 PMID:17911618 PMID:17982082

    Open questions at the time
    • Mechanistic interplay among these repressors not integrated
    • Direct vs indirect cofactor effects on CIITA not all resolved
  10. 2008 High

    Revealed that CIITA induction is controlled through long-range chromatin architecture, with BRG1-dependent distal enhancers and pre-existing chromatin loops.

    Evidence ChIP combined with chromosome conformation capture (3C) in BRG1-deficient cells with histone modification analysis

    PMID:18500344

    Open questions at the time
    • Architectural proteins establishing the loops not identified
    • Mechanism of BRG1-independent pre-existing loops unknown
  11. 2011 High

    Identified lineage- and maturation-specific control of CIITA and the post-translational acetylation switch, and uncovered CIITA's antiviral and immunoregulatory moonlighting functions.

    Evidence PU.1/HSS1 3C and shRNA; PRDM1/G9a/HDAC2 footprinting in IRF8-null DCs; SIRT1 deacetylation/proteasome/ChIP assays; Tax-1 co-IP and LTR reporter; CIITA-/- DC IL-10 reporter

    PMID:15661876 PMID:20363966 PMID:21216962 PMID:21813598 PMID:21890893

    Open questions at the time
    • How DC maturation triggers PRDM1 recruitment unresolved
    • Specificity determinants of CIITA acetylation sites not mapped
  12. 2017 Medium

    Established arginine methylation as a bidirectional regulator of CIITA, with PRMT1 driving degradation and PRMT5 potentiating transcription, and defined the genome-wide CIITA binding landscape.

    Evidence Co-IP and in vitro methylation with PRMT1/PRMT5 gain/loss-of-function and ChIP; genome-wide ChIP-seq with CRISPR-null validation

    PMID:25753668 PMID:26972221 PMID:28094290

    Open questions at the time
    • Methylated residues on CIITA not precisely mapped
    • Distinction between CIITA binding and functional regulation incompletely defined
  13. 2020 High

    Defined NFAT5-dependent myeloid CIITA control, the FBXO11 E3 ligase as the major determinant of CIITA half-life, and effector mechanisms of CIITA in viral restriction, vascular gene silencing, and bone remodeling.

    Evidence NFAT5-KO macrophage ChIP-seq with graft rejection; FBXO11 proteomics, ubiquitination and cycloheximide chase; CD74 p41 viral entry/cathepsin assays; SUV39H1 co-IP/ChIP at eNOS; H3K14ac ChIP in osteocytes; HIV-1 Tat LTR reporter

    PMID:27089879 PMID:30327417 PMID:30716531 PMID:32855215 PMID:35760800 PMID:37279268

    Open questions at the time
    • Signals selecting CIITA for FBXO11 ubiquitination not defined
    • Mechanism by which CIITA switches between activator and SUV39H1-recruiting repressor unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse post-translational modifications (phosphorylation, acetylation, arginine methylation, ubiquitination) are integrated to set CIITA activity, stability, and its choice between activator and repressor roles remains unresolved.
  • No unified model linking PTM crosstalk to functional output
  • Structural basis of CIITA assembly at the enhanceosome not determined
  • Determinants of activator vs repressor mode unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140223 general transcription initiation factor activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3
Partners
CREBFBXO11NFYBNFYCRFX5RFXANKSIRT1ZXDC

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CIITA expression is induced by IFN-γ, and transfection of CIITA is sufficient to activate MHC class II gene expression in class II-negative cells in the absence of IFN-γ, establishing CIITA as a general regulator of both inducible and constitutive MHC class II expression. Transfection of CIITA into class II-negative cells; IFN-γ stimulation assays Science High 8016643
1994 CIITA mediates IFN-γ induction of HLA-DR and invariant chain (Ii) genes; a mutant cell line (G3A) selectively defective in HLA-DR and Ii induction lacks functional CIITA, and a second mutant (G1B) lacking RFX DNA-binding activity also fails to induce DRA and Ii genes by IFN-γ, linking RFX to the IFN-γ response. Analysis of IFN-γ mutant cell lines; genetic complementation Immunity High 7600294
1995 Both CIITA and RFX5 are essential regulators of HLA-DMA and HLA-DMB gene expression (constitutive and IFN-γ-inducible), with each cDNA able to correct the respective regulatory mutant defect. Genetic complementation of regulatory mutant cell lines by cDNA transfection International immunology High 7495736
1997 The CIITA gene is controlled by multiple distinct promoters: one directing constitutive expression in dendritic cells, one in B lymphocytes, and one mediating IFN-γ-induced expression, explaining cell-type-specific and inducible MHC class II expression. Promoter-specific reporter assays; cell-type expression analysis The EMBO journal High 9184229
1997 A dominant-negative CIITA mutant lacking the N-terminal acidic activation domain represses constitutive and IFN-γ-induced MHC class II expression of all three isotypes (HLA-DR, HLA-DQ, HLA-DP), but in a CIITA-deficient B cell line, HLA-DQ expression is not altered, revealing both CIITA-dependent and CIITA-independent class II regulatory pathways. Dominant-negative CIITA transfection; anti-CIITA monoclonal antibodies; CIITA-deficient cell lines Journal of immunology High 9144488
1998 RFX5 and RFXAP subunits of the RFX complex are required for both constitutive and CIITA-induced MHC class I and beta2-microglobulin transactivation, and the X1 box within the S-X-Y promoter region is critical for this regulation. Functional analysis in type III bare lymphocyte syndrome cell lines lacking RFX subunits Immunity High 9806639
1998 MHC class II gene silencing in trophoblast cells is caused by inability to induce CIITA expression (not by absence of RFX/X2BP factors or IFN-γ signaling pathway defects); transfection of CIITA into trophoblast cells restores MHC class II expression. Transfection rescue assay; expression analysis of MHC class II transcription factors in trophoblast cell lines American journal of reproductive immunology High 11053628 9894561
2000 CIITA leucine-rich repeats (LRRs) are required for nuclear localization and in vivo recruitment to the MHC class II promoter (shown by chromatin immunoprecipitation); LRR alanine mutations abolish transactivation capacity and dominant-negative phenotype. CIITA directly interacts with RFX5, RFXANK, NF-YB, and NF-YC through LRR-independent protein-protein interactions. A novel 33 kDa protein interacts with CIITA in an LRR-sensitive manner. LRR alanine mutagenesis; chromatin immunoprecipitation; co-immunoprecipitation; nuclear localization assays Molecular and cellular biology High 11003667
2000 Lack of CIITA expression in trophoblast cells is due to hypermethylation of the IFN-γ-inducible promoter IV (PIV) of CIITA; introduction of exogenous CIITA induces MHC class I and II surface expression and antigen presentation capacity. Bisulfite methylation analysis of CIITA PIV; CIITA transfection rescue; antigen presentation assay Human immunology High 11053628
2001 CIITA forms homomeric complexes with itself through a central region including the GTP-binding domain; LXXLL motifs in the GTP-binding domain are essential for self-association. The central region also interacts with the C-terminal LRR and N-terminal acidic domain. CIITA mutants differ in activation function, subcellular localization, and dominant-negative potential. Co-immunoprecipitation; deletion/point mutagenesis; subcellular localization assays Molecular and cellular biology Medium 11438649
2002 IFN-γ induction of CIITA from promoter IV (PIV) requires sequential binding of STAT1 (within 30 min, accompanied by modest histone H3/H4 acetylation) followed by IRF-1 synthesis and binding (>120 min) before CIITA mRNA is detected. Fetal trophoblast-like cells refractory to CIITA induction fail to assemble these factors; bisulfite sequencing shows strong PIV hypermethylation in these cells. Chromatin immunoprecipitation kinetics; bisulfite sequencing; IFN-γ stimulation time course Molecular and cellular biology High 12052885
2002 BRG1, the ATPase subunit of the SWI/SNF chromatin-remodeling complex, is required for IFN-γ induction of CIITA; reconstitution with BRG1 but not an ATPase-deficient mutant (K798R) rescues CIITA induction. BRG1 interacts directly with the endogenous CIITA promoter in an IFN-γ-inducible fashion, and its activity is required for chromatin remodeling at the CIITA locus. BRG1/hBRM-deficient cell lines; BRG1 reconstitution; chromatin immunoprecipitation; DNase I footprinting; restriction enzyme accessibility The EMBO journal High 11953317
2002 CIITA regulates MHC class II transcription initiation by recruiting CDK7 and CDK9 kinases and enhancing CDK7-mediated phosphorylation of RNA Pol II at Ser5, promoting promoter clearance. CIITA is recruited to the DRA enhanceosome after IFN-γ, leading to recruitment of CBP and GCN5 coactivators, histone acetylation, and SWI/SNF recruitment. Chromatin immunoprecipitation temporal analysis; kinase activity assays; IFN-γ stimulation time course The EMBO journal High 14517250
2002 The enhanceosome (RFX complex) and CIITA make variable, promoter-dependent contributions to histone acetylation and recruitment of TBP, TFIIB, and RNA Pol II; CIITA is generally required at multiple levels of the activation process across four co-regulated MHC class II genes. Chromatin immunoprecipitation in RFX-deficient and CIITA-deficient cell lines; analysis of four MHC-II promoters The EMBO journal High 11889043
2003 CIITA activates expression of the semaphorin receptor plexin-A1 in dendritic cells; plexin-A1 is required for T cell stimulation by antigen-pulsed DCs but not for peptide binding to MHC. This was identified by cDNA microarray in CIITA-deficient mice and confirmed by shRNA knockdown. cDNA microarray; shRNA knockdown; T cell stimulation assays; CIITA-deficient and MHC class II-deficient mouse DCs Nature immunology High 12910265
2004 CIITA contains acetyltransferase (AT) and kinase activities that contribute to MHC class I and II gene transcription; as a general transcription factor, CIITA can functionally replace the TFIID component TAF1 with parallel substrate specificity and regulatory features. Biochemical activity assays; functional complementation; mutagenesis (reviewed with experimental support cited within) Frontiers in immunology (review of experimental findings) Medium 24391648
2004 Phosphorylation of CIITA at serine residues 286, 288, and 293 downregulates CIITA activity; the nuclear form of CIITA is predominantly phosphorylated whereas cytoplasmic CIITA is predominantly unphosphorylated. Double mutations at these sites increase nuclear CIITA and enhance endogenous MHC class II expression. Serine-to-alanine mutagenesis; subcellular fractionation; endogenous MHC class II expression assays; phosphorylation site mapping Journal of immunology Medium 15210796
2004 RFX and CIITA bind to novel distal S'-Y' modules located far from known MHC-II gene promoters; these elements function as transcriptional enhancers that are bona fide targets of RFX and CIITA in B cells and IFN-γ-induced cells, inducing broad domains of histone hyperacetylation. Computational S-Y motif identification; chromatin immunoprecipitation; reporter assays; histone acetylation ChIP Journal of immunology Medium 15528357
2006 Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced CIITA expression by TLR2-induced MAPK (p38 and ERK) signaling, which causes histone hypoacetylation at CIITA promoter IV and suppression of BRG1 recruitment; this effect is absent in TLR2-deficient macrophages. Chromatin immunoprecipitation; TLR2 knockout macrophages; MAPK inhibitors (p38, ERK); histone acetylation assays Journal of immunology High 16547269
2006 EZH2, a component of Polycomb repressive complex 2, is present at CIITA promoter IV chromatin in uveal melanoma cells and is associated with trimethylation of H3K27; RNAi-mediated knockdown of EZH2 increases IFN-γ-inducible CIITA transcript levels. Chromatin immunoprecipitation; RNAi knockdown; histone methylation analysis (3Me-K27-H3) Journal of immunology Medium 17911618
2006 M. tuberculosis 19-kDa lipoprotein induces C/EBPβ and C/EBPδ binding to CIITA promoters I and IV, correlating with inhibition of IFN-γ-induced CIITA expression; constitutive expression of C/EBPβ LIP isoform inhibits IFN-γ-induced CIITA expression. Chromatin immunoprecipitation; oligodeoxynucleotide pulldown; transfection of C/EBPβ LIP; quantitative RT-PCR Journal of immunology Medium 17982082
2006 ZXDC, a novel zinc finger protein, interacts with the LRR-containing region of CIITA; overexpression of ZXDC super-activates MHC class I and class II promoters by CIITA, and ZXDC silencing reduces CIITA-dependent MHC class II transcription. Yeast two-hybrid; co-immunoprecipitation; overexpression and shRNA knockdown reporter assays Molecular immunology Medium 16600381
2007 ZXDA and ZXDC form a heterocomplex (as well as homodimers) through their zinc finger-containing regions; the ZXDA-ZXDC complex interacts with CIITA and is important for MHC class II gene transcription; ZXDC is present at MHC class II promoters before and after IFN-γ treatment. Co-immunoprecipitation; knockdown and overexpression assays; chromatin immunoprecipitation Journal of molecular biology Medium 17493635
2008 BRG1 regulates IFN-γ-mediated CIITA induction through many interdependent distal enhancers rather than through the promoter alone; at uninduced CIITA, BRG1-independent chromatin loops pre-exist, and IFN-γ-induced recruitment of STAT1, IRF1, p300, and histone modifications at distal elements all show BRG1 dependency. Chromatin immunoprecipitation; chromosome conformation capture (3C); BRG1-deficient cells; histone modification analysis Nature immunology High 18500344
2010 PU.1 binds a distal regulatory element (HSS1, 11 kb upstream of CIITA pIII) required for B cell-specific CIITA expression; chromatin conformation capture shows HSS1 physically interacts with CIITA pIII in B cells through PU.1-mediated chromatin looping; PU.1 depletion reduces CIITA expression. DNase I hypersensitivity; chromatin immunoprecipitation; chromatin conformation capture (3C); shRNA knockdown; bacterial artificial chromosome reporter assays Journal of immunology High 20363966
2011 CIITA inhibits HTLV-1 replication by physically interacting with the viral transactivator Tax-1 (via CIITA residues 1-252 and 253-410 interacting with Tax-1 residues 1-108); only CIITA residues 1-252 mediate Tax-1 inhibition. CIITA impairs the physical and functional interaction of Tax-1 with cellular coactivators PCAF, CREB, and ATF1, required for optimal HTLV-1 LTR activation. Co-immunoprecipitation in vivo; deletion mutagenesis; HTLV-1 LTR luciferase reporter assay; coactivator overexpression rescue Journal of virology High 21813598
2011 CIITA negatively regulates IL-10 expression in dendritic cells; CIITA-deficient DCs produce increased IL-10 mRNA and protein, while reintroduction of CIITA into CIITA-/- DCs reduces IL-10 production; co-transfection of CIITA with an IL-10 promoter-reporter decreases IL-10 promoter activity. CIITA-/- mouse DCs; CIITA reconstitution; IL-10 promoter-reporter assay; LPS/CpG stimulation Journal of immunology Medium 15661876
2011 PRDM1/Blimp-1 silences CIITA expression in maturing dendritic cells by recruiting co-repressors G9a and HDAC2 to CIITA promoter I, causing loss of histone acetylation and acquisition of H3K9 dimethylation and HP1γ; IRF8/PU.1 heterodimer binding is required for CIITApI activation in immature DCs and is blocked by PRDM1. In vivo genomic footprinting; chromatin immunoprecipitation; IRF8-null mouse DCs; PRDM1 reporter assays; DC maturation model Journal of biological chemistry High 21216962
2011 SIRT1 deacetylase interacts with and deacetylates CIITA; SIRT1 activation augments MHC II transcription by protecting CIITA from proteasomal degradation and promoting nuclear accumulation and promoter binding; SIRT1 depletion increases CIITA acetylation and attenuates its activity. Stress stimuli (hypobaric hypoxia, oxLDL) induce CIITA acetylation and suppress its activity by inhibiting SIRT1. Co-immunoprecipitation; deacetylation assay; proteasome inhibition; nuclear fractionation; chromatin immunoprecipitation; SIRT1 activator/inhibitor treatment Nucleic acids research High 21890893
2015 Genome-wide ChIP-seq reveals CIITA binds 480 sites in B cells, predominantly at active promoters and enhancers containing accessible chromatin; CIITA binding correlates with increased H3K27 acetylation at non-regulated loci, suggesting a chromatin-poising function; computational modeling of XY box motifs defines sequence constraints distinguishing CIITA-mediated regulation from mere binding. ChIP-seq; CIITA-null cell lines (including CRISPR/Cas9-generated); histone modification analysis; computational motif modeling Nucleic acids research High 25753668
2016 CIITA inhibits HIV-1 replication in myeloid (U937) cells by targeting the viral transactivator Tat to inhibit Tat-dependent HIV-1 LTR transactivation; this is independent of TRIM22 expression. Overexpression of CIITA in permissive U937 Plus cells restores suppression of Tat transactivation. Stable CIITA overexpression; HIV-1 LTR luciferase reporter assay; reverse transcriptase activity measurement; flow cytometry; western blot Journal of translational medicine Medium 27089879
2017 PRMT1 methylates CIITA and promotes CIITA proteasomal degradation, thereby repressing MHC class II transcription in macrophages; IFN-γ treatment downregulates PRMT1 expression and attenuates PRMT1 binding to the MHC II promoter; PRMT1 overexpression represses while PRMT1 depletion enhances MHC II transactivation. Co-immunoprecipitation; in vitro methylation assay; chromatin immunoprecipitation; PRMT1 overexpression and knockdown; MHC II promoter reporter assay Scientific reports Medium 28094290
2016 PRMT5 interacts with CIITA and is recruited by CIITA to the MHC II promoter; PRMT5 potentiates IFN-γ-induced MHC II transcription in an enzyme activity-dependent manner by symmetrically dimethylating H3R2 (H3R2Me2s) and mediating synergy between PRMT5 and ASH2/WDR5; PRMT5 silencing or inhibition suppresses MHC II transactivation. Co-immunoprecipitation; chromatin immunoprecipitation; PRMT5 overexpression and knockdown; enzyme activity inhibitor (MTA); histone methylation assay Biochimica et biophysica acta Medium 26972221
2018 NFAT5 is required for expression of CIITA and MHC class II in macrophages (but not dendritic cells); NFAT5-deficient macrophages show defective CD4+ T cell activation and impaired graft rejection in vivo. NFAT5 regulates a distal upstream enhancer of Ciita that physically interacts with the Ciita myeloid promoter I and exhibits NFAT5-dependent H3K27 acetylation. NFAT5-deficient macrophages; CHIP-seq (ultrasequencing of NFAT5-immunoprecipitated chromatin); H3K27 acetylation ChIP; in vivo graft rejection model; CD4+ T cell activation assay Journal of experimental medicine High 30327417
2019 CIITA interacts with and recruits the histone H3K9 trimethyltransferase SUV39H1 to the eNOS promoter, resulting in H3K9Me3 enrichment and transcriptional repression of eNOS in endothelial cells in response to IFN-γ; CIITA depletion normalizes H3K4Me3 and H3K9Me3 at the eNOS promoter; SUV39H1 silencing abrogates IFN-γ-induced eNOS repression. Chromatin immunoprecipitation; co-immunoprecipitation; CIITA overexpression and knockdown; SUV39H1 knockdown; histone methylation analysis (H3K9Me3, H3K4Me3) Biochimica et biophysica acta. Gene regulatory mechanisms Medium 30716531
2020 CIITA induces resistance to Ebola virus by activating expression of the p41 isoform of the invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein; CD74 p41 also blocks the endosomal entry pathway of SARS-CoV-2 and other coronaviruses. Transposon-mediated gene-activation screen; CD74 p41 expression; viral entry assays; cathepsin activity assays; CIITA and CD74 gain-of-function Science High 32855215
2023 FBXO11, a member of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex, is a binding partner and E3 ligase for CIITA; FBXO11 promotes ubiquitin-dependent proteasomal degradation of CIITA and is the major regulator of CIITA half-life. FBXO11 expression reduces MHC class II promoter activity, transcript levels, and surface expression through CIITA downregulation; FBXO11-deficient cells display increased MHC II and related genes. Unbiased proteomics for CIITA-binding proteins; cycloheximide chase assay; ubiquitination assay; MHC II promoter reporter; flow cytometry; FBXO11-deficient human and mouse cells Proceedings of the National Academy of Sciences High 37279268
2022 In osteocytes, CIITA upregulates secretion of osteolytic cytokines (RANKL/TNFSF11 and sclerostin/SOST) through histone H3K14 acetylation at their promoters, promoting osteoclastogenesis and decreasing osteoblastogenesis; myeloma cell-secreted 2-deoxy-D-ribose upregulates CIITA expression in osteocytes through STAT1/IRF1 signaling. Chromatin immunoprecipitation (H3K14 acetylation); CIITA overexpression in osteocytes; osteoclastogenesis assays; STAT1/IRF1 pathway analysis Nature communications Medium 35760800
2006 CREB and phospho-CREB interact with CIITA and with the RFX5 subunit of the RFX complex through the C-terminal portion of CREB; phospho-CREB is found at the HLA-DRA promoter by ChIP; phosphorylation of CREB enhances but is not required for transcription from MHC-II promoter reporters. Co-immunoprecipitation with CREB mutants; reporter assays; chromatin immunoprecipitation Molecular immunology Medium 16730065

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science (New York, N.Y.) 763 8016643
2011 MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 479 21368758
1997 Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. The EMBO journal 395 9184229
2005 MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nature genetics 256 15821736
2004 Mini-review: Specificity and expression of CIITA, the master regulator of MHC class II genes. European journal of immunology 235 15162420
2006 Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. Journal of immunology (Baltimore, Md. : 1950) 172 16547269
2006 Epigenetic regulation of MHC-II and CIITA genes. Trends in immunology 164 16870508
1994 Molecular analysis of G1B and G3A IFN gamma mutants reveals that defects in CIITA or RFX result in defective class II MHC and Ii gene induction. Immunity 128 7600294
2003 CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nature immunology 111 12910265
2013 CIITA and Its Dual Roles in MHC Gene Transcription. Frontiers in immunology 100 24391648
2020 MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science (New York, N.Y.) 99 32855215
2015 Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell reports 98 26549456
2002 Kinetics of a gamma interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Molecular and cellular biology 98 12052885
2008 Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. The Journal of clinical endocrinology and metabolism 94 18593762
1998 The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes. Immunity 92 9806639
2000 CIITA leucine-rich repeats control nuclear localization, in vivo recruitment to the major histocompatibility complex (MHC) class II enhanceosome, and MHC class II gene transactivation. Molecular and cellular biology 91 11003667
1995 The two novel MHC class II transactivators RFX5 and CIITA both control expression of HLA-DM genes. International immunology 91 7495736
2002 Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent. The EMBO journal 90 11953317
2008 The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers. Nature immunology 88 18500344
2019 CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine. Frontiers in immunology 85 31417570
2005 Epigenetic control of MHC-II: interplay between CIITA and histone-modifying enzymes. Current opinion in immunology 82 15653312
2011 Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects. Experimental & molecular medicine 77 21464590
2013 Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma. Immunology 76 23789844
1998 Mice lacking the transcription factor CIITA--a second look. International immunology 75 9885917
2003 CIITA regulates transcription onset viaSer5-phosphorylation of RNA Pol II. The EMBO journal 72 14517250
2021 The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins. International journal of molecular sciences 68 33499042
2000 Lack of CIITA expression is central to the absence of antigen presentation functions of trophoblast cells and is caused by methylation of the IFN-gamma inducible promoter (PIV) of CIITA. Human immunology 60 11053628
2007 CCAAT/enhancer-binding protein beta and delta binding to CIITA promoters is associated with the inhibition of CIITA expression in response to Mycobacterium tuberculosis 19-kDa lipoprotein. Journal of immunology (Baltimore, Md. : 1950) 55 17982082
2018 Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5. The Journal of experimental medicine 53 30327417
2007 A role for EZH2 in silencing of IFN-gamma inducible MHC2TA transcription in uveal melanoma. Journal of immunology (Baltimore, Md. : 1950) 53 17911618
2004 Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA. Journal of immunology (Baltimore, Md. : 1950) 51 15528357
2011 Positive regulatory domain I (PRDM1) and IRF8/PU.1 counter-regulate MHC class II transactivator (CIITA) expression during dendritic cell maturation. The Journal of biological chemistry 50 21216962
1997 CIITA-dependent and -independent class II MHC expression revealed by a dominant negative mutant. Journal of immunology (Baltimore, Md. : 1950) 49 9144488
2001 Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN-gamma-inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4(+) T-cell activation. Glia 48 11746775
2002 Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. The EMBO journal 47 11889043
2019 Class II transactivator (CIITA) mediates IFN-γ induced eNOS repression by enlisting SUV39H1. Biochimica et biophysica acta. Gene regulatory mechanisms 45 30716531
2013 Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA. Journal of immunology (Baltimore, Md. : 1950) 45 23776173
1999 Differential selectivity of CIITA promoter activation by IFN-gamma and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affected by TNF-alpha. Journal of neuroimmunology 44 10505975
2006 Role of the MHC2TA gene in autoimmune diseases. Annals of the rheumatic diseases 43 17012290
2005 Enhanced production of IL-10 by dendritic cells deficient in CIITA. Journal of immunology (Baltimore, Md. : 1950) 43 15661876
2002 Regulation and specificity of MHC2TA promoter usage in human primary T lymphocytes and cell line. Journal of immunology (Baltimore, Md. : 1950) 43 12218128
2010 CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis. Human molecular genetics 42 20211854
2002 Transcriptional regulation of the MHC class II trans-activator (CIITA) promoter III: identification of a novel regulatory region in the 5'-untranslated region and an important role for cAMP-responsive element binding protein 1 and activating transcription factor-1 in CIITA-promoter III transcriptional activation in B lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 41 12391222
2005 Differential expression of MHC class II molecules in highly metastatic breast cancer cells is mediated by the regulation of the CIITA transcription Implication of CIITA in tumor and metastasis development. The international journal of biochemistry & cell biology 40 16343978
1999 Human parainfluenza virus type 3 up-regulates major histocompatibility complex class I and II expression on respiratory epithelial cells: involvement of a STAT1- and CIITA-independent pathway. Journal of virology 39 9882346
2007 MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. Molecular immunology 38 17300840
1998 MHC class II gene silencing in trophoblast cells is caused by inhibition of CIITA expression. American journal of reproductive immunology (New York, N.Y. : 1989) 38 9894561
2020 Generation of GGTA1-/-β2M-/-CIITA-/- Pigs Using CRISPR/Cas9 Technology to Alleviate Xenogeneic Immune Reactions. Transplantation 37 32732833
2001 Self-association of CIITA and its transactivation potential. Molecular and cellular biology 37 11438649
2020 Helicobacter pylori Dampens HLA-II Expression on Macrophages via the Up-Regulation of miRNAs Targeting CIITA. Frontiers in immunology 34 31969878
2011 Major histocompatibility complex class II transactivator CIITA is a viral restriction factor that targets human T-cell lymphotropic virus type 1 Tax-1 function and inhibits viral replication. Journal of virology 34 21813598
2008 Alterations in CIITA constitute a common mechanism accounting for downregulation of MHC class II expression in diffuse large B-cell lymphoma (DLBCL). Experimental hematology 34 19081173
2005 Expression of the MHC class II transactivator (CIITA) type IV promoter in B lymphocytes and regulation by IFN-gamma. Molecular immunology 32 15950283
2008 Enhancement of DNA vaccine potency through coadministration of CIITA DNA with DNA vaccines via gene gun. Journal of immunology (Baltimore, Md. : 1950) 31 18453624
2011 SIRT1 links CIITA deacetylation to MHC II activation. Nucleic acids research 30 21890893
2017 Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA. Scientific reports 29 28094290
2015 Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment. Nucleic acids research 29 25753668
2006 MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency. The Journal of clinical endocrinology and metabolism 29 16849401
2021 CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens. Molecular & cellular proteomics : MCP 28 33592498
2010 PU.1 binds to a distal regulatory element that is necessary for B cell-specific expression of CIITA. Journal of immunology (Baltimore, Md. : 1950) 28 20363966
2007 Environment-gene interaction in multiple sclerosis: human herpesvirus 6 and MHC2TA. Human immunology 28 17678724
2006 Epigenetic regulation during B cell differentiation controls CIITA promoter accessibility. Journal of immunology (Baltimore, Md. : 1950) 28 16951349
2023 The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy. Biomedical journal 26 37467968
2018 CIITA-related block of HLA class II expression, upregulation of HLA class I, and heterogeneous expression of immune checkpoints in hepatocarcinomas: implications for new therapeutic approaches. Oncoimmunology 26 30723578
2016 The MHC-II transactivator CIITA inhibits Tat function and HIV-1 replication in human myeloid cells. Journal of translational medicine 25 27089879
2009 Irradiated CIITA-positive mammary adenocarcinoma cells act as a potent anti-tumor-preventive vaccine by inducing tumor-specific CD4+ T cell priming and CD8+ T cell effector functions. International immunology 25 19395374
2007 The MHC2TA -168A/G polymorphism and risk for rheumatoid arthritis: a meta-analysis of 6861 patients and 9270 controls reveals no evidence for association. Annals of the rheumatic diseases 25 17875550
2006 Epigenetic silencing of MHC2TA transcription in cancer. Biochemical pharmacology 25 16879803
2004 Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 25 15210796
2020 In Primitive Zebrafish, MHC Class II Expression Is Regulated by IFN-γ, IRF1, and Two Forms of CIITA. Journal of immunology (Baltimore, Md. : 1950) 24 32188757
2009 MHC2TA rs4774C and HHV-6A active replication in multiple sclerosis patients. European journal of neurology 24 19659749
2006 ZXDC, a novel zinc finger protein that binds CIITA and activates MHC gene transcription. Molecular immunology 24 16600381
2023 FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA. Proceedings of the National Academy of Sciences of the United States of America 23 37279268
2012 CIITA is silenced by epigenetic mechanisms that prevent the recruitment of transactivating factors in rhabdomyosarcoma cells. International journal of cancer 23 21989738
2011 The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus. Genes and immunity 23 21614020
2007 The zinc finger proteins ZXDA and ZXDC form a complex that binds CIITA and regulates MHC II gene transcription. Journal of molecular biology 23 17493635
2004 Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells. Investigative ophthalmology & visual science 23 15326139
2000 Synergistic induction of HLA class I expression by RelA and CIITA. Blood 23 10845913
2021 Induction of CIITA by IFN-γ in macrophages involves STAT1 activation by JAK and JNK. Immunobiology 22 34303919
2017 Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration. Neurobiology of disease 22 28736195
2004 A CIITA-independent pathway that promotes expression of endogenous rather than exogenous peptides in immune-privileged sites. European journal of immunology 22 14768052
2023 LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer. Cellular signalling 21 38168631
2015 A2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells. Biochimica et biophysica acta 21 25765819
2013 Exosomes from CIITA-transfected CT26 cells enhance anti- tumor effects. Asian Pacific journal of cancer prevention : APJCP 21 23621273
2006 CREB and phospho-CREB interact with RFX5 and CIITA to regulate MHC class II genes. Molecular immunology 21 16730065
2016 The arginine methyltransferase PRMT5 regulates CIITA-dependent MHC II transcription. Biochimica et biophysica acta 20 26972221
2012 CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations. Genes and immunity 20 22513452
2009 Roles of PU.1 in monocyte- and mast cell-specific gene regulation: PU.1 transactivates CIITA pIV in cooperation with IFN-gamma. International immunology 20 19502584
2006 Investigation of the MHC2TA gene, associated with rheumatoid arthritis in a Swedish population, in a UK rheumatoid arthritis cohort. Arthritis and rheumatism 20 17075826
2006 The MHC2TA -168A>G gene polymorphism is not associated with rheumatoid arthritis in Austrian patients. Arthritis research & therapy 19 16776848
2006 MHC2TA promoter polymorphism (-168*G/A, rs3087456) is not associated with susceptibility to rheumatoid arthritis in British Caucasian rheumatoid arthritis patients. Rheumatology (Oxford, England) 19 16920747
2005 Constitutive expression of CIITA directs CD4 T cells to produce Th2 cytokines in the thymus. Cellular immunology 19 15876426
2005 Lack of MHC-II expression in activated mouse T cells correlates with DNA methylation at the CIITA-PIII region. Immunogenetics 19 16235089
2004 T cell expression of CIITA represses Th1 immunity. International immunology 19 15351782
2022 Osteocyte CIITA aggravates osteolytic bone lesions in myeloma. Nature communications 18 35760800
2008 CIITA versus IFN-gamma induced MHC class II expression in head and neck cancer cells. Archives of dermatological research 18 19104823
2013 Epigenetic modulation of RFC1, MHC2TA and HLA-DR in systemic lupus erythematosus: association with serological markers and six functional polymorphisms of one-carbon metabolic pathway. Gene 17 24333266
2006 Polymorphism in the MHC2TA gene is associated with features of the metabolic syndrome and cardiovascular mortality. PloS one 17 17183695
2002 Single nucleotide polymorphisms in MHC2TA, the gene encoding the MHC class II transactivator (CIITA). Genes and immunity 17 11857059
1999 Cis-element dependence and occupancy of the human invariant chain promoter in CIITA-dependent and -independent transcription. Molecular immunology 17 10449097

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