Affinage

CIITA

MHC class II transactivator · UniProt P33076

Length
1130 aa
Mass
123.4 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIITA is the master transcriptional coactivator of MHC class II genes and a key regulator of MHC class I expression, functioning as a non-DNA-binding NLR-family protein that nucleates an enhanceosome at conserved S-X-Y promoter modules by interacting with the DNA-binding factors RFX5, RFXANK, NF-Y, and CREB (PMID:7749984, PMID:9177217, PMID:11889043). CIITA is expressed from cell-type-specific promoters whose induction by IFN-γ requires STAT1/IRF1 signaling and BRG1/SWI/SNF-dependent chromatin remodeling at distal enhancers, and it drives transcription initiation by recruiting P-TEFb (CDK9/Cyclin T1) and CDK7 to phosphorylate RNA Pol II Ser5, while coordinating histone acetyltransferases and deacetylases to control promoter acetylation state (PMID:8016643, PMID:11953317, PMID:18500344, PMID:10661406, PMID:14517250). CIITA activity is regulated post-translationally by acetylation (PCAF/CBP; counteracted by SIRT1), phosphorylation at Ser286/288/293, arginine methylation by PRMT1 promoting degradation, and FBXO11-mediated ubiquitin-proteasomal turnover, all of which modulate its nuclear accumulation and enhanceosome occupancy (PMID:11046145, PMID:21890893, PMID:28094290, PMID:37279268). Beyond antigen presentation, CIITA acts as a viral restriction factor—competing with HIV Tat for P-TEFb binding, blocking HTLV-1 Tax-1-dependent NF-κB activation, and inducing CD74 p41-dependent resistance to Ebola virus and SARS-CoV-2 entry—and represses non-immune genes including collagen and IL-10 (PMID:10661406, PMID:21813598, PMID:26792751, PMID:32855215, PMID:15247294).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 High

    The identity of the factor controlling MHC class II induction was unknown; transfection of CIITA into class II-negative cells restored MHC-II expression without IFN-γ, establishing CIITA as the master regulator of both constitutive and inducible MHC class II transcription.

    Evidence Gain-of-function transfection rescue in class II-negative cells with IFN-γ stimulation assays

    PMID:8016643

    Open questions at the time
    • Mechanism by which CIITA activates transcription without directly binding DNA was unknown
    • Whether CIITA controlled MHC class I was not addressed
  2. 1995 High

    How CIITA activates MHC-II promoters without DNA binding was unclear; domain analysis showed CIITA acts as a coactivator that directs activity through the X box element and nucleates a higher-order complex, possessing a potent activation domain but no DNA-binding capacity.

    Evidence Transfection with wild-type and mutant CIITA; gel-shift/complex formation assays at X box

    PMID:7749984

    Open questions at the time
    • Identity of the DNA-binding partner(s) that tether CIITA to the promoter was not resolved
    • Activation domain targets were unknown
  3. 1997 High

    How CIITA is tethered to promoters and how its expression is diversified across cell types were open questions; RFX5 was identified as the direct DNA-binding partner providing promoter specificity, and three cell-type-specific promoters were mapped, explaining constitutive versus inducible expression patterns.

    Evidence Yeast two-hybrid and far-Western for RFX5 interaction; promoter-reporter assays in dendritic cells, B cells, and IFN-γ-treated cells

    PMID:9177217 PMID:9184229

    Open questions at the time
    • Other enhanceosome components (NF-Y, CREB) had not yet been characterized as CIITA partners
    • How CIITA interfaces with the general transcription machinery was unknown
  4. 1997 High

    Whether CIITA regulated genes beyond MHC class II was untested; CIITA was shown to transactivate MHC class I genes through the site alpha element, broadening its role to the entire antigen presentation pathway.

    Evidence Transfection of CIITA into class I-deficient cells; promoter mutant reporters; IFN-γ induction in CIITA-induction-defective G3A cells

    PMID:9175837 PMID:9175838

    Open questions at the time
    • Whether CIITA uses the same enhanceosome at class I versus class II promoters was unclear
    • RFX requirement for class I activation was not yet demonstrated
  5. 1998 High

    The requirement for the RFX complex at MHC class I and β2m promoters was uncertain; complementation of RFX-deficient BLS patient cells showed that RFX5/RFXAP and the X1 box are essential for CIITA-dependent transactivation of both MHC-I and MHC-II genes.

    Evidence Genetic complementation in type III BLS cells; promoter mutant reporters

    PMID:9806639

    Open questions at the time
    • How the full enhanceosome assembles in ordered steps was not resolved
    • Whether additional cofactors beyond RFX are needed for class I activation was unclear
  6. 2000 High

    How CIITA connects to the transcription elongation/initiation machinery was unknown; CIITA was found to bind P-TEFb (Cyclin T1/CDK9) on the same surface used by HIV Tat, and CIITA was simultaneously shown to be acetylated by PCAF/CBP to regulate its nuclear-cytoplasmic shuttling.

    Evidence Competition binding assays and RNA-tethered transcription for P-TEFb; in vitro acetylation assays with mutagenesis and subcellular fractionation for acetylation

    PMID:10661406 PMID:11046145

    Open questions at the time
    • Whether P-TEFb recruitment leads to Pol II CTD phosphorylation at CIITA target promoters was not shown
    • Kinases responsible for CIITA's own phosphorylation were unidentified
  7. 2000 High

    The contribution of the leucine-rich repeat (LRR) domain was undefined; LRR mutations abolished nuclear localization and in vivo promoter recruitment (by ChIP) without disrupting direct RFX5 binding, establishing the LRR as essential for nuclear import and chromatin-level function.

    Evidence LRR alanine mutagenesis; ChIP; nuclear localization microscopy; pull-down with enhanceosome components

    PMID:11003667

    Open questions at the time
    • Whether LRRs sense a ligand analogous to other NLR proteins was not addressed
    • Structural basis of LRR-mediated nuclear import was not resolved
  8. 2001 Medium

    Whether CIITA functions as a monomer or oligomer was unknown; CIITA was shown to self-associate through its GTP-binding domain via LXXLL motifs, suggesting oligomerization is integral to its activity.

    Evidence Yeast two-hybrid; co-immunoprecipitation; domain-deletion analysis

    PMID:11438649

    Open questions at the time
    • Stoichiometry of the oligomer was not determined
    • Whether GTP binding/hydrolysis regulates oligomerization was untested
    • Not independently confirmed by a second laboratory
  9. 2002 High

    How CIITA expression is epigenetically induced at its own locus was unclear; BRG1 was shown to be recruited to the CIITA promoter in an IFN-γ-dependent manner, and its ATPase activity was required for chromatin remodeling permitting CIITA transcription.

    Evidence ChIP for BRG1; reconstitution with ATPase-dead K798R mutant; DNase I footprinting and restriction enzyme accessibility

    PMID:11953317

    Open questions at the time
    • Whether BRG1 acts directly or is recruited by a specific transcription factor at the CIITA locus was not defined
    • Distal regulatory elements had not been mapped
  10. 2003 High

    The temporal order of cofactor recruitment and the mechanism of transcription initiation at MHC-II promoters were unresolved; CIITA was shown to recruit CDK7 and CDK9, enhancing Ser5 phosphorylation of RNA Pol II to initiate transcription, while ubiquitination of CIITA enhanced enhanceosome association and HDAC1 antagonized it.

    Evidence ChIP-based temporal dissection; kinase activity assays; ubiquitination assays; co-IP of HDAC1/mSin3A with CIITA; HAT/HDAC inhibitor experiments

    PMID:12697811 PMID:14517250 PMID:14528304

    Open questions at the time
    • The E3 ubiquitin ligase responsible for activating ubiquitination of CIITA was not identified
    • Whether CIITA ubiquitination is degradative or non-degradative in this context was ambiguous
  11. 2003 High

    Whether CIITA controlled non-MHC target genes was largely unexplored; microarray analysis of CIITA-deficient DCs identified plexin-A1 as a CIITA target whose knockdown impaired T cell stimulation, revealing CIITA's role in DC–T cell communication beyond antigen presentation.

    Evidence cDNA microarray in CIITA-deficient vs. control DCs; shRNA knockdown of plexin-A1; T cell stimulation assays

    PMID:12910265

    Open questions at the time
    • Whether CIITA directly binds the plexin-A1 promoter was not shown
    • Breadth of non-MHC targets was not systematically assessed
  12. 2004 High

    Dual roles of CIITA as both activator and repressor at different loci were emerging; CIITA was found to repress collagen COL1A2 transcription by displacing RNA Pol II from the promoter via RFX5-mediated recruitment, while phosphorylation at Ser286/288/293 was shown to negatively regulate nuclear CIITA activity.

    Evidence ChIP and shRNA at COL1A2 promoter; site-directed mutagenesis of serine residues with endogenous MHC-II readout and nuclear fractionation

    PMID:11889043 PMID:15210796 PMID:15247294

    Open questions at the time
    • Kinase(s) phosphorylating Ser286/288/293 were not identified
    • Whether collagen repression occurs in non-smooth-muscle cell contexts was untested
  13. 2006 High

    Pathogen evasion of CIITA and additional CIITA cofactors were being characterized; M. tuberculosis 19-kDa lipoprotein was found to silence CIITA via TLR2-MAPK-driven histone hypoacetylation at promoter IV, and CREB/phospho-CREB were shown to directly interact with CIITA and RFX5 to enhance enhanceosome function.

    Evidence ChIP in TLR2-/- macrophages with MAPK inhibitors; co-IP of CREB deletion mutants with CIITA; phospho-CREB ChIP

    PMID:16547269 PMID:16730065

    Open questions at the time
    • Whether other pathogens use the same TLR2-MAPK-CIITA silencing axis was unknown
    • Structural basis of CREB–CIITA interaction was not resolved
  14. 2008 High

    How the CIITA locus is regulated at the three-dimensional chromatin level was unknown; BRG1 was found to be recruited to distal enhancers that loop to the CIITA promoter, establishing a hierarchical model in which BRG1-dependent histone activation marks precede STAT1/IRF1/p300 recruitment.

    Evidence ChIP-seq; chromosome conformation capture (3C); BAC deletion analysis of distal elements

    PMID:18500344

    Open questions at the time
    • Whether additional transcription factors cooperate at the distal enhancer was not fully resolved
    • 3D looping dynamics during IFN-γ signaling were not captured in real time
  15. 2011 High

    Post-translational control of CIITA stability and non-immune functions of CIITA were expanding; SIRT1 was identified as a CIITA deacetylase that stabilizes CIITA and promotes MHC-II expression, while CIITA was shown to inhibit myogenesis by binding myogenin and displacing Pol II from muscle gene promoters.

    Evidence Co-IP and deacetylation assays for SIRT1–CIITA; ChIP at muscle-specific promoters; CIITA overexpression/knockdown in myoblasts

    PMID:21576360 PMID:21890893

    Open questions at the time
    • Whether SIRT1-CIITA axis operates in professional APCs in vivo was not tested
    • CIITA's role in muscle physiology under non-inflammatory conditions was not explored
  16. 2011 High

    Whether CIITA had direct antiviral functions beyond MHC upregulation was unknown; CIITA was found to physically interact with HTLV-1 Tax-1 and impair Tax-1 association with PCAF, CREB, and ATF1, thereby blocking HTLV-1 LTR activation.

    Evidence Domain-mapping co-IP; luciferase LTR reporter; coactivator overexpression rescue

    PMID:21813598

    Open questions at the time
    • Whether this restriction operates in primary HTLV-1-infected T cells was not demonstrated
    • Mechanism by which CIITA displaces coactivators from Tax-1 was not structurally resolved
  17. 2014 High

    The genome-wide binding landscape of CIITA was unknown; ChIP-seq revealed ~800 CIITA binding intervals covering >400 genes, 95% outside the MHC, with 60% lacking RFX5, establishing that CIITA has widespread RFX-independent genomic occupancy and can poise chromatin via H3K27 acetylation.

    Evidence ChIP-seq in primary B cells and monocytes; CRISPR/Cas9 CIITA-null cells with RNA-seq; eQTL and allele-specific ChIP

    PMID:25366989 PMID:25753668

    Open questions at the time
    • Functional significance of CIITA binding at most non-MHC sites was not determined
    • RFX-independent recruitment mechanism was not identified
  18. 2016 High

    How CIITA restricts HTLV-1-driven NF-κB signaling was mechanistically unresolved; CIITA was found to act at both cytoplasmic and nuclear levels—retaining Tax-1 in an inactive IκB complex in the cytoplasm and sequestering Tax-1/RelA in nuclear bodies—while PRMT5 was identified as a CIITA-recruited histone arginine methyltransferase that promotes MHC-II activation.

    Evidence Subcellular fractionation and nuclear body imaging for Tax-1/NF-κB; co-IP and ChIP with enzyme-dead PRMT5 mutant for MHC-II

    PMID:26792751 PMID:26972221

    Open questions at the time
    • Whether CIITA-mediated NF-κB inhibition affects other NF-κB-dependent viral or cellular programs was not explored
    • Relative contribution of PRMT5 versus other histone modifiers at MHC-II promoters was not quantified
  19. 2018 High

    Macrophage-specific regulation of the CIITA locus was poorly understood; NFAT5 was found to bind and activate a remote upstream enhancer of Ciita that loops to macrophage-specific promoter I, with NFAT5-dependent H3K27 acetylation controlling macrophage MHC-II expression and graft rejection in vivo.

    Evidence NFAT5-deficient macrophages; ChIP-seq; 3C; in vivo graft rejection assay

    PMID:30417417

    Open questions at the time
    • Whether NFAT5-CIITA axis is relevant in human macrophages was not shown
    • Signals activating NFAT5 at the CIITA enhancer were not defined
  20. 2020 High

    Whether CIITA could restrict viral entry independently of adaptive immunity was unknown; a genome-wide screen identified CIITA-driven expression of CD74 p41 as a mechanism blocking cathepsin-dependent processing required for Ebola virus and SARS-CoV-2 entry, establishing CIITA as an innate antiviral restriction factor.

    Evidence Transposon-mediated gene-activation screen; CIITA/CD74 knockdown and overexpression; viral infection assays with cathepsin inhibitors

    PMID:32855215

    Open questions at the time
    • Whether CD74 p41-mediated restriction operates in primary macrophages or DCs during natural infection was not tested
    • Breadth of viruses susceptible to this mechanism was not determined
  21. 2023 High

    The E3 ligase controlling CIITA proteasomal turnover was unidentified; FBXO11 was discovered by unbiased proteomics as an SCF-type E3 ligase that ubiquitinates CIITA and determines its protein half-life, with FBXO11 deficiency increasing MHC-II expression at transcript, promoter, and surface levels.

    Evidence Unbiased proteomic identification; co-IP; cycloheximide chase; FBXO11 knockout cells; MHC-II reporter and surface expression

    PMID:37279268

    Open questions at the time
    • Specific lysine residues on CIITA targeted by FBXO11 were not mapped
    • Whether FBXO11 and the previously described activating ubiquitination represent distinct ubiquitin chain types was not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of enhanceosome assembly, whether GTP binding/hydrolysis by the NLR-type domain regulates CIITA activity, the functional impact of CIITA at the majority of its genome-wide binding sites outside the MHC, and the in vivo significance of CIITA's antiviral restriction functions during natural infection.
  • No high-resolution structure of CIITA or its enhanceosome exists
  • GTPase activity and potential ligand sensing by the NLR domain are functionally uncharacterized
  • Biological significance of RFX-independent genome-wide CIITA binding remains undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0098772 molecular function regulator activity 3 GO:0016740 transferase activity 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-4839726 Chromatin organization 4
Partners
CCNT1CDK9FBXO11HDAC1PCAFRFX5RFXANKSIRT1
Complex memberships
MHC-II enhanceosome (RFX5/RFXANK/NF-Y/CREB/CIITA)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CIITA expression is controlled and 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 the general regulator of both inducible and constitutive MHC class II expression. Transfection rescue experiments in class II-negative cells; IFN-γ stimulation assays Science High 8016643
1997 The CIITA gene is controlled by multiple distinct promoters: one directing constitutive expression in dendritic cells, one in B lymphocytes, and a third mediating IFN-γ-induced expression, explaining the cellular and functional diversity of MHC-II expression. Promoter-reporter transfection assays; cell-type-specific expression analysis The EMBO journal High 9184229
1995 CIITA functions as a coactivator that directs its transcriptional activity through the X box element of MHC class II promoters; CIITA leads to formation of a higher-order complex at the X box region and contains a potent activation domain but does not bind DNA directly. DNA-mediated transfection with wild-type and mutant CIITA; gel-shift/complex formation assays Immunity High 7749984
1997 CIITA directly interacts with RFX5, a DNA-binding protein of the MHC class II regulatory complex, as demonstrated by yeast two-hybrid and far-Western assays; RFX5 determines promoter specificity via its DNA-binding domain while CIITA recruits the general transcription apparatus via its acidic activation domain. Yeast two-hybrid assay; far-Western blot; GAL4 fusion cotransfection in B cells and HeLa cells; complementation of CIITA-deficient RJ2.2.5 cells Proceedings of the National Academy of Sciences of the United States of America High 9177217
1997 CIITA transactivates MHC class I gene expression through the site alpha DNA element; IFN-γ-induced MHC class I expression requires intact site alpha, and cells defective in CIITA induction (G3A) fail to induce MHC class I. Transfection of class I-deficient cell lines with CIITA; promoter mutant reporter assays; dominant-negative CIITA experiments; IFN-γ induction in G3A cells Immunity High 9175837 9175838
2000 CIITA binds to P-TEFb (Cyclin T1/CDK9 complex) through the same surface on Cyclin T1 used by HIV Tat; a dominant-negative CDK9 inhibits MHC II promoter activity, and CIITA activates transcription when tethered to RNA, establishing CIITA as a cellular coactivator that uses P-TEFb for target gene expression. Competition binding assays; dominant-negative CDK9 reporter assays; RNA-tethered transcription assay Immunity High 10661406
2000 CIITA is acetylated at lysine residues within its nuclear localization signal by PCAF and CBP; acetylation regulates CIITA nuclear accumulation (shuttling between nucleus and cytoplasm), and mutagenesis of acetylated lysines reduces transactivation ability. Co-IP of CIITA with PCAF/CBP in vivo and in vitro; acetylation assays; trichostatin A treatment; mutagenesis of acetylated residues; nuclear/cytoplasmic fractionation Molecular and cellular biology High 11046145
2000 The leucine-rich repeat (LRR) region of CIITA is required for nuclear localization, in vivo recruitment to MHC class II promoters, and transactivation; LRR mutations abolish CIITA-RFX5 binding at the promoter (by ChIP) but not direct protein-protein interaction with RFX5 in pull-down, suggesting LRRs primarily govern nuclear import with an additional direct role in transcription. LRR alanine mutagenesis; chromatin immunoprecipitation (ChIP); nuclear localization microscopy; co-immunoprecipitation/pull-down with RFX5, RFXANK, NF-YB, NF-YC Molecular and cellular biology High 11003667
2001 CIITA forms homo-oligomeric complexes with itself; the central GTP-binding domain is sufficient for self-association; LXXLL motifs in the GTP-binding domain are essential for self-association; and distinct regions mediate nuclear localization, activation function, and dominant-negative activity. Yeast two-hybrid; co-immunoprecipitation; domain-deletion analysis; subcellular localization assays Molecular and cellular biology Medium 11438649
2002 BRG1, the ATPase subunit of the SWI/SNF chromatin-remodeling complex, is required for IFN-γ induction of CIITA; BRG1 interacts directly with the CIITA promoter in an IFN-γ-inducible manner (by ChIP), and an ATPase-dead BRG1 (K798R) fails to rescue CIITA induction, demonstrating that catalytic chromatin-remodeling activity is required. Chromatin immunoprecipitation; BRG1 reconstitution with wild-type vs. ATPase-dead mutant; DNase I footprinting; restriction enzyme accessibility assay The EMBO journal High 11953317
2003 CIITA ubiquitination enhances its association with MHC class II transcription factors and with the MHC class II promoter, resulting in increased transactivation; the degree of CIITA ubiquitination is controlled by histone acetyltransferases (HATs) and deacetylases (HDACs). Ubiquitination assays; co-immunoprecipitation; ChIP; HAT/HDAC inhibitor treatments Nature immunology High 14528304
2003 HDAC1 (in complex with mSin3A) physically associates with CIITA and suppresses CIITA-dependent MHC class II transcription by disrupting enhanceosome assembly (reducing NF-YB and RFX5 association with CIITA) and reducing H3 acetylation at MHC class II promoters. Co-immunoprecipitation of endogenous CIITA with HDAC1; GAL4-CIITA fusion reporter assay; ChIP for H3 acetylation and enhanceosome components; HDAC inhibitor (trichostatin A) treatment Molecular and cellular biology High 12697811
2003 CIITA regulates transcription initiation at MHC class II genes by recruiting CDK7 and CDK9 kinases and enhancing CDK7-mediated phosphorylation of RNA Pol II at Ser5, leading to initiation of mRNA synthesis; CIITA is recruited to the enhanceosome, which subsequently recruits CBP and GCN5 coactivators and the SWI/SNF remodeling complex. Chromatin immunoprecipitation; temporal order analysis; kinase activity assays The EMBO journal High 14517250
2004 CIITA mediates IFN-γ-induced repression of collagen COL1A2 transcription; CIITA occupies the COL1A2 transcription start site in vivo (ChIP), is recruited there by RFX5, and displaces RNA polymerase II; shRNA knockdown of CIITA alleviates COL1A2 repression while also preventing MHC-II activation. ChIP; DNA affinity chromatography; shRNA knockdown; CIITA domain-deletion constructs with collagen promoter reporters The Journal of biological chemistry High 15247294
2004 CIITA phosphorylation at serine residues 286, 288, and 293 in its nuclear-localized form down-regulates CIITA activity; mutations at these sites increase nuclear CIITA accumulation and enhance endogenous MHC class II expression from chromatin but not from plasmid-based promoters. Site-directed mutagenesis of serine residues; nuclear/cytoplasmic fractionation; endogenous MHC class II expression assays; promoter reporter assays Journal of immunology Medium 15210796
2003 Plexin-A1 is a novel transcriptional target of CIITA in dendritic cells; plexin-A1 knockdown by shRNA reduces T cell stimulation by antigen-pulsed DCs without affecting antigen processing or MHC peptide binding, defining a CIITA-dependent function in T cell–DC interaction. cDNA microarray of CIITA-deficient vs. control DCs; shRNA knockdown of plexin-A1; T cell stimulation assays Nature immunology High 12910265
2011 CIITA binds to myogenin and inhibits its activity in IFN-γ-treated myoblasts; CIITA is recruited to muscle-specific gene promoters coincident with reductions in RNA polymerase II recruitment, inhibiting myogenesis in both a gene-repression and protein-activity-inhibitory manner. Co-IP of CIITA with myogenin; ChIP at muscle-specific promoters; CIITA overexpression and shRNA knockdown; IFN-γ treatment of myoblasts and myotubes Molecular and cellular biology High 21576360
2011 CIITA inhibits HTLV-1 replication by blocking the transactivating function of Tax-1; CIITA physically interacts with Tax-1 via CIITA residues 1–252 and 253–410 (and Tax-1 amino acids 1–108), and impairs Tax-1 association with coactivators PCAF, CREB, and ATF1 required for HTLV-1 LTR activation. Co-immunoprecipitation mapping of interaction domains; luciferase LTR reporter assay; overexpression rescue with PCAF/CREB/ATF1 Journal of virology High 21813598
2016 CIITA inhibits Tax-1-mediated NF-κB activation at both cytoplasmic and nuclear levels: in the cytoplasm, CIITA retains Tax-1 and maintains the inactive p50/RelA/IκB complex; in the nucleus, CIITA associates with Tax-1/RelA in nuclear bodies to block NF-κB-responsive gene activation; CIITA interacts with Tax-1 without preventing Tax-1 binding to IKKγ or RelA but affects Tax-1-induced IKK activity. Subcellular fractionation; co-immunoprecipitation; NF-κB reporter assays; IKK activity assays; nuclear body imaging with cytoplasmic/nuclear mutant CIITA forms Journal of virology High 26792751
2020 CIITA induces resistance to Ebola virus and SARS-CoV-2 by activating expression of the CD74 p41 isoform, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein and the endosomal entry pathway of coronaviruses. Transposon-mediated gene-activation screen; CIITA/CD74 knockdown and overexpression; viral infection assays; mechanistic dissection with cathepsin inhibitors Science High 32855215
2006 Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced CIITA expression through TLR2-dependent MAPK (p38/ERK) signaling that causes histone hypoacetylation at CIITA promoter IV and blocks recruitment of the BRG1 chromatin-remodeling protein to this promoter. Chromatin immunoprecipitation for histone acetylation; TLR2-/- macrophages; MAPK inhibitors (p38/ERK); BRG1 ChIP Journal of immunology High 16547269
2008 BRG1 regulates CIITA induction through multiple interdependent distal enhancers rather than through the promoter alone; BRG1 is recruited to a far upstream site, triggering a histone activation mark that is prerequisite for subsequent IFN-γ-induced recruitment of STAT1, IRF1, and p300, and for chromatin looping. ChIP-seq; chromosome conformation capture (3C); deletion analysis of distal elements in BAC constructs Nature immunology High 18500344
2011 SIRT1 deacetylates CIITA, protecting it from proteasomal degradation and promoting its nuclear accumulation and target promoter binding, thereby enhancing MHC class II transcription; stress stimuli (hypoxia, oxLDL) inhibit SIRT1 and increase CIITA acetylation, suppressing MHC II activation. Co-immunoprecipitation; deacetylation assays; proteasome inhibitor treatments; SIRT1 overexpression/silencing; ChIP; cellular fractionation Nucleic acids research High 21890893
2017 PRMT1 interacts with CIITA, methylates CIITA, and promotes CIITA degradation, thereby repressing MHC class II transcription; IFN-γ treatment down-regulates PRMT1 expression and attenuates its binding at the MHC II promoter. Co-immunoprecipitation; in vitro methylation assay; PRMT1 overexpression and knockdown; ChIP; CIITA stability assays Scientific reports Medium 28094290
2019 CIITA recruits the histone H3K9 trimethyltransferase SUV39H1 to the eNOS promoter to repress eNOS transcription in endothelial cells; IFN-γ stimulation promotes CIITA occupancy on the eNOS promoter coincident with loss of H3K4Me3 and gain of H3K9Me3. ChIP assays for CIITA, SUV39H1, and histone marks; co-immunoprecipitation of CIITA with SUV39H1; CIITA overexpression/knockdown; SUV39H1 silencing Biochimica et biophysica acta. Gene regulatory mechanisms Medium 30716531
2016 PRMT5 interacts with CIITA and is recruited by CIITA to the MHC class II promoter; PRMT5 promotes H3R2 symmetric dimethylation at the MHC II promoter and synergizes with ASH2/WDR5 to activate MHC II transcription in an enzyme-activity-dependent manner. Co-immunoprecipitation; ChIP for PRMT5 and H3R2Me2s; PRMT5 overexpression and knockdown; enzyme-activity mutant Biochimica et biophysica acta Medium 26972221
2007 EZH2, the histone H3K27 trimethyltransferase component of Polycomb repressive complex 2, is present at the CIITA promoter IV chromatin in uveal melanoma cells; high H3K27Me3 at this promoter correlates with reduced RNA Pol II recruitment and impaired IFN-γ-induced CIITA transcription; EZH2 knockdown restores CIITA induction. Chromatin immunoprecipitation for H3K27Me3 and EZH2; RNA Pol II ChIP; EZH2 siRNA knockdown Journal of immunology Medium 17911618
2023 FBXO11, a member of the Skp1-Cullin-1-F-box E3 ligase complex, binds CIITA (identified by unbiased proteomics), ubiquitinates CIITA, and regulates CIITA protein half-life through the ubiquitin-proteasome system; FBXO11 deficiency increases MHC class II expression at the promoter, transcript, and surface levels. Unbiased proteomic identification of CIITA-binding proteins; co-immunoprecipitation; cycloheximide chase assay; FBXO11 knockout cells; MHC-II reporter and surface expression assays Proceedings of the National Academy of Sciences of the United States of America High 37279268
2018 NFAT5 is required for CIITA and MHC class II expression specifically in macrophages (not dendritic cells); NFAT5 binds and activates a remote upstream enhancer of the Ciita locus that loops to interact with the myeloid Ciita promoter I, and this enhancer shows NFAT5-dependent H3K27 acetylation. NFAT5-deficient macrophages; ChIP-seq (NFAT5 immunoprecipitation); chromosome conformation capture; histone modification ChIP; in vivo graft rejection assay The Journal of experimental medicine High 30327417
1998 The RFX complex (including RFX5 and RFXAP) is required for both constitutive and CIITA-induced MHC class I, MHC class II, and beta2-microglobulin transactivation, and the X1 box within the S-X-Y region is the critical cis-element mediating CIITA-dependent transactivation of MHC class I and beta2m promoters. Type III BLS cell lines lacking RFX; promoter mutant reporter assays; complementation with RFX5 and RFXAP expression constructs Immunity High 9806639
2006 CIITA in complex with RFX5 mediates IFN-γ-induced repression of collagen type I gene transcription in smooth muscle cells; IFN-γ increases nuclear levels of CIITA isoforms III and IV in SMCs correlating with decreased collagen type I and increased MHC II gene expression. CIITA isoform transfection; nuclear fractionation; COL1A promoter reporter assays; ChIP implied by previous work; RFX5 knockdown by simvastatin treatment Circulation research Medium 16439692
2013 CIITA possesses intrinsic acetyltransferase (AT) and kinase activities that contribute to MHC class I and II gene transcription; as a general transcription factor, CIITA functionally replaces the TFIID component TAF1, and its AT and kinase substrate specificities parallel those of TAF1. Review integrating enzymatic activity assays (acetyltransferase and kinase), mutagenesis data, and functional transcription assays from multiple studies Frontiers in immunology Medium 24391648
2014 Genome-wide ChIP-seq mapping reveals 843 CIITA binding intervals covering 442 genes (95% outside the MHC), including histone gene clusters; 60% of intervals lack RFX5 binding, indicating CIITA can be recruited independently of the canonical enhanceosome at non-MHC loci; allele-specific NF-κB recruitment mediates trans-regulation by a CIITA intronic variant. ChIP-seq in primary human B cells and monocytes; eQTL mapping; allele-specific ChIP Genome biology High 25366989
2015 Genome-wide CIITA ChIP-seq in Raji B cells identifies 480 binding sites predominantly at active promoters/enhancers; CIITA binding at non-regulated loci is associated with increased H3K27 acetylation, suggesting CIITA poises chromatin at these sites; computational modeling identifies XY-box sequence constraints that distinguish CIITA-regulated from merely CIITA-bound sites. ChIP-seq; CRISPR/Cas9-generated CIITA-null cells; RNA-seq in CIITA-null cells; computational sequence modeling Nucleic acids research High 25753668
2006 CIITA negatively regulates IL-10 expression in dendritic cells; CIITA co-transfection with an IL-10 promoter reporter decreases IL-10 promoter activity, and reintroduction of CIITA into CIITA-/- DCs reduces IL-10 production, establishing a transcriptional repressor function of CIITA beyond MHC class II regulation. CIITA-/- mouse DCs; IL-10 promoter-reporter transfection; CIITA reconstitution; ELISA and RT-PCR Journal of immunology Medium 15661876
2004 CIITA, RFX, and CREB interact to form the MHC class II enhanceosome; RFX and CIITA make variable, promoter-dependent contributions to histone acetylation, TBP, TFIIB, and RNA Pol II recruitment across four co-regulated MHC class II family genes. ChIP for histones H3/H4 acetylation, TBP, TFIIB, Pol II in RFX-deficient and CIITA-deficient cells across multiple promoters The EMBO journal High 11889043
2006 CREB and phospho-CREB interact directly with both CIITA and the RFX5 subunit through the C-terminal domain of CREB; phosphorylation of CREB enhances MHC class II promoter transcription; phospho-CREB occupancy at the HLA-DRA promoter was detected by ChIP. Co-immunoprecipitation with CREB deletion mutants; reporter assays; ChIP 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.) 757 8016643
2011 MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471 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 394 9184229
2004 Mini-review: Specificity and expression of CIITA, the master regulator of MHC class II genes. European journal of immunology 232 15162420
2000 Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 226 10661406
1997 Site alpha is crucial for two routes of IFN gamma-induced MHC class I transactivation: the ISRE-mediated route and a novel pathway involving CIITA. Immunity 177 9175838
1997 Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 176 9175837
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) 171 16547269
1995 Activation of class II MHC genes requires both the X box region and the class II transactivator (CIITA). Immunity 165 7749984
2006 Epigenetic regulation of MHC-II and CIITA genes. Trends in immunology 163 16870508
2000 Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Molecular and cellular biology 133 11046145
2003 CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nature immunology 111 12910265
1997 Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5. Proceedings of the National Academy of Sciences of the United States of America 111 9177217
1998 Quantitative control of MHC class II expression by the transactivator CIITA. European journal of immunology 110 9521055
2013 CIITA and Its Dual Roles in MHC Gene Transcription. Frontiers in immunology 98 24391648
2020 MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science (New York, N.Y.) 97 32855215
2004 Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells. Oncogene 96 15467734
2008 Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. The Journal of clinical endocrinology and metabolism 94 18593762
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
1998 The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes. Immunity 91 9806639
1995 The two novel MHC class II transactivators RFX5 and CIITA both control expression of HLA-DM genes. International immunology 90 7495736
2002 Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent. The EMBO journal 89 11953317
2008 The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers. Nature immunology 88 18500344
2006 CIITA-induced MHC class II expression in mammary adenocarcinoma leads to a Th1 polarization of the tumor microenvironment, tumor rejection, and specific antitumor memory. Clinical cancer research : an official journal of the American Association for Cancer Research 88 16740768
2003 Enhancement of CIITA transcriptional function by ubiquitin. Nature immunology 87 14528304
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 82 31417570
2005 Epigenetic control of MHC-II: interplay between CIITA and histone-modifying enzymes. Current opinion in immunology 82 15653312
2003 Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation. Molecular and cellular biology 81 12697811
2011 Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects. Experimental & molecular medicine 76 21464590
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
2011 Gamma interferon modulates myogenesis through the major histocompatibility complex class II transactivator, CIITA. Molecular and cellular biology 68 21576360
2021 The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins. International journal of molecular sciences 64 33499042
2004 Cutting edge: induction of the antigen-processing enzyme IFN-gamma-inducible lysosomal thiol reductase in melanoma cells Is STAT1-dependent but CIITA-independent. Journal of immunology (Baltimore, Md. : 1950) 63 15240658
1995 CIITA activates the expression of MHC class II genes in mouse T cells. International immunology 63 7495759
2006 Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells. Circulation research 56 16439692
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
2004 Major histocompatibility class II transactivator (CIITA) mediates repression of collagen (COL1A2) transcription by interferon gamma (IFN-gamma). The Journal of biological chemistry 50 15247294
1997 CIITA-dependent and -independent class II MHC expression revealed by a dominant negative mutant. Journal of immunology (Baltimore, Md. : 1950) 49 9144488
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
2004 E47, IRF-4, and PU.1 synergize to induce B-cell-specific activation of the class II transactivator promoter III (CIITA-PIII). Blood 45 15242870
2011 Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. Human molecular genetics 43 21653641
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
2008 The IFN-gamma-induced transcriptional program of the CIITA gene is inhibited by statins. European journal of immunology 38 18601229
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
2015 Characterization of NLR-A subfamily members in miiuy croaker and comparative genomics revealed NLRX1 underwent duplication and lose in actinopterygii. Fish & shellfish immunology 37 26381931
2007 MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. Molecular immunology 37 17300840
2001 Self-association of CIITA and its transactivation potential. Molecular and cellular biology 37 11438649
2020 Generation of GGTA1-/-β2M-/-CIITA-/- Pigs Using CRISPR/Cas9 Technology to Alleviate Xenogeneic Immune Reactions. Transplantation 36 32732833
2016 The Major Histocompatibility Complex Class II Transactivator CIITA Inhibits the Persistent Activation of NF-κB by the Human T Cell Lymphotropic Virus Type 1 Tax-1 Oncoprotein. Journal of virology 36 26792751
2014 Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach. Genome biology 35 25366989
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 Identification of CIITA regulated genetic module dedicated for antigen presentation. PLoS genetics 34 18437201
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
2003 Class II transactivator (CIITA) promoter methylation does not correlate with silencing of CIITA transcription in trophoblasts. Biology of reproduction 33 12748124
2020 Helicobacter pylori Dampens HLA-II Expression on Macrophages via the Up-Regulation of miRNAs Targeting CIITA. Frontiers in immunology 32 31969878
2005 Expression of the MHC class II transactivator (CIITA) type IV promoter in B lymphocytes and regulation by IFN-gamma. Molecular immunology 32 15950283
2013 IRF-4-mediated CIITA transcription is blocked by KSHV encoded LANA to inhibit MHC II presentation. PLoS pathogens 31 24204280
2002 Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. Immunogenetics 31 11862382
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
2006 MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency. The Journal of clinical endocrinology and metabolism 29 16849401
2015 Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment. Nucleic acids research 28 25753668
2011 Early epigenetic events regulate the adaptive immune response gene CIITA. Epigenetics 28 21266852
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) 27 16951349
2016 The MHC-II transactivator CIITA inhibits Tat function and HIV-1 replication in human myeloid cells. Journal of translational medicine 25 27089879
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
1996 Induction of CIITA and modification of in vivo HLA-DR promoter occupancy in normal thymic epithelial cells treated with IFN-gamma: similarities and distinctions with respect to HLA-DR-constitutive B cells. Journal of immunology (Baltimore, Md. : 1950) 25 8666795
2023 The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy. Biomedical journal 24 37467968
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
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 24 17875550
2000 Synergistic induction of HLA class I expression by RelA and CIITA. Blood 23 10845913
2017 Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration. Neurobiology of disease 22 28736195
2011 The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus. Genes and immunity 22 21614020
2004 A CIITA-independent pathway that promotes expression of endogenous rather than exogenous peptides in immune-privileged sites. European journal of immunology 22 14768052
2004 Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells. Investigative ophthalmology & visual science 22 15326139
2003 Human trophoblast noncoding RNA suppresses CIITA promoter III activity in murine B-lymphocytes. Biochemical and biophysical research communications 22 12565840
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 21 37279268
2021 Induction of CIITA by IFN-γ in macrophages involves STAT1 activation by JAK and JNK. Immunobiology 21 34303919
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
2012 Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes. Genes and immunity 21 23052709
1999 Downregulation of HLA class I gene transcription in choriocarcinoma cells is controlled by the proximal promoter element and can be reversed by CIITA. Placenta 21 10329350
2020 NLR-A Simple Indicator of Inflammation for the Diagnosis of Left Ventricular Hypertrophy in Patients with Hypertension. International heart journal 20 32173694
2016 The arginine methyltransferase PRMT5 regulates CIITA-dependent MHC II transcription. Biochimica et biophysica acta 20 26972221
2006 CREB and phospho-CREB interact with RFX5 and CIITA to regulate MHC class II genes. Molecular immunology 20 16730065
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
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 19 38168631
2006 The MHC2TA -168A>G gene polymorphism is not associated with rheumatoid arthritis in Austrian patients. Arthritis research & therapy 19 16776848
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