NOD-kaltainen reseptori NLRA, joka on MHCII geenien transaktivaatttori: CIITA (16p13.13)

CIITA ( 16p13.13).
Tämän geenin synonyyminimiä ovat  C2TAN, MHC2TA, NLRA.
PubMed lähde kertoo tästä geenistä:
Selventävä artikkeli ja kuva   CIITA isoformin IF3  transaktivaattorifunktiosta
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613680/
Tiivistelmä:
MHCluokkaII:n transaktivaattori CIITA ( NLRA)   tunnetaan   MHCII molekyylien  mestarisäätelijänä.  Tämä NLRA säätyy  sofististen posttranslatioaalisten  modifikaatioitten sarjasta. Sen tehtävänä on aloittaa MHCII-geenien transkriptio; MHCII-geeneistä koodautuvat  tekijät   kantavat vastuuta  extrasellulaaristen antigeenien esittämisestä T-CD4+ lymfosyyteille.

• Abstract The class II transactivator (CIITA) is known as the master regulator for the major histocompatibility class II (MHC II) molecules. CIITA is dynamically regulated through a series of intricate post-translational modifications (PTMs). CIITA's role is to initiate transcription of MHC II genes, which are responsible for presenting extracellular antigen to CD4⁺ T-cells

Tässä tutkimuksessa  tunnistettiin  ERK1/2 kinaasit  transaktivaattorin  säätelyllisen kohdan Ser 280:n fosforyloijiksi. Tämän seriinin fosfopryloituminen johtaa monoubikitinaation lisääntymiseen ja MCHII-aktiivisuuden yleiseen kasvuun. 

Tutkijat havaitsivat että  CIITA modifioituu myös   myös lysiinin K63 ubikitinaatiolla , K63-ubikitinoitua CIITA:ta konsentroituu sytoplasmaan ja sitä translokoituu tumaan.  Sen ubikitinaatiot ja fosforylaatiot heijastavat sitä. miten posttranslationaalinen modifikaatio vaikuttaa sen sijaintiin ja säätelylliseen aktiivisuuteen . Tuntematon E3-ligaasi  tekee  K63 ubikitinaation. ei olle varmoja jos tämä tapahtuu sytoplasmassa   tai tumassa. Sillä on merkitys  MHCII geenien ylössäädössä  Runsaantuvasta  tumassa tapahtuvasta fosforylaatiosta seuraa lisää  monoubikitinaatiota, mikä  taas  säätää CIITA  funktiota alas ja vaikuttaa  lopulta  sen siirtymistä pois tumasta sytoplasmaan,  mahdolliseen proteosomaaliseen hajoitukseen.  On tärkeää  tunnistaa   CIITA:n posttranslationaaliset modifikaatiot    CIITA säätelyn välittäjinä , sillä  tällä NRLA-geenituotteella  on kriittinen osuus adaptatiivisten immuunivasteiden alkamisessa.

. In the present study, we identified extracellular signal-regulated kinase (ERK)1/2 as the kinase responsible for phosphorylating the regulatory site, Ser²⁸⁰, which leads to increased levels of mono-ubiquitination and an overall increase in MHC II activity. Further, we identify that CIITA is also modified by Lys⁶³-linked ubiquitination. Lys⁶³ ubiquitinated CIITA is concentrated in the cytoplasm and following activation of ERK1/2, CIITA phosphorylation occurs and Lys=ubiquitinated CIITA translocates to the nucleus. CIITA ubiquitination and phosphorylation perfectly demonstrates how CIITA location and activity is regulated through PTM cross-talk. Identifying CIITA PTMs and understanding how they mediate CIITA regulation is necessary due to the critical role CIITA has in the initiation of the adaptive immune response.

 
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https://www.ncbi.nlm.nih.gov/gene/4261
Suomennosta
Tämä geeni koodaa proteiinia jossa on AD_domeeni ( hapan transkriptionaalinen aktivaatiodomeeni),  4 kappaletta  LRR-toistojaksjaoa ( runsaaasti leusiinia sisältäviä jaksoja)  ja GTP:tä sitova domeeni. Proteiini sijoittautuu tumaan ja toimii positiivisena säätelijänä luokan II  MHC histokompatibiliteettikompleksigeenin  transkription säätelyssä. Sitä kutsutaankin  mestarikontrollantiksi  (master controlfactor) näiden geenien ilementymisessä.  Proteiini sitoo myös GTP-energiapakkauksia ja käyttää GTP-energiaa  nopeuttaakseen omaa kuljetustaan tumaan. Tumassa ollessaan se ei sitoudu DNA- materiaa , vaan pikemminkin käyttää sisäistä asyylitransferaasiaktiivisuuttaan (AT) toimien koaktivaatorin tapaisesti.
Tämän geenin mutaatioita  liittyy  perinnölliseen MCH II-luokan vajeeseen tai HLA II-luokan vajeeseen liittyvään immuunipuutteeseen,  nivelreuma-alttiuden, MS- alttiuden ja   sydäninfarktialttiuden  lisääntymiseen.   geeniä ilmenee pernassa, imusolmukkeissa ja 19 muussa kudoksessa.

• Also known as C2TA; NLRA; MHC2TA; CIITAIV
•  Preferred Names

  MHC class II transactivator

  Names

  MHC class II transactivator type I

  MHC class II transactivator type III

  NLR family, acid domain containing

  nucleotide-binding oligomerization domain, leucine rich repeat and acid domain containing

• Summary This gene encodes a protein with an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain. The protein is located in the nucleus and acts as a positive regulator of class II major histocompatibility complex gene transcription, and is referred to as the "master control factor" for the expression of these genes. The protein also binds GTP and uses GTP binding to facilitate its own transport into the nucleus. Once in the nucleus it does not bind DNA but rather uses an intrinsic acetyltransferase (AT) activity to act in a coactivator-like fashion. Mutations in this gene have been associated with bare lymphocyte syndrome type II (also known as hereditary MHC class II deficiency or HLA class II-deficient combined immunodeficiency), increased susceptibility to rheumatoid arthritis, multiple sclerosis, and possibly myocardial infarction. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]
• Expression Broad expression in spleen (RPKM 12.7), lymph node (RPKM 11.9) and 19 other tissues 

Lisäartikkeleita tästä geenistä löytyy PubMed lähteessä.
GeneRif antaa myös lisää  detaljitietoja tästä geenistä.

• Related articles in PubMed

1. Fowlpoxvirus recombinants coding for the CIITA gene increase the expression of endogenous MHC-II and Fowlpox Gag/Pro and Env SIV transgenes. Bissa M, et al. PLoS One, 2018. PMID 29385169, Free PMC Article
2. Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Mottok A, et al. Cell Rep, 2015 Nov 17. PMID 26549456
3. Association between the functional MHC2TA -168 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis. Lee YH, et al. Clin Rheumatol, 2016 Apr. PMID 26439834
4. Polycomb recruitment at the Class II transactivator gene. Boyd NH, et al. Mol Immunol, 2015 Oct. PMID 26283540
5. The class II transactivator (CIITA) is regulated by post-translational modification cross-talk between ERK1/2 phosphorylation, mono-ubiquitination and Lys63 ubiquitination. Morgan JE, et al. Biosci Rep, 2015 Jun 19. PMID 26181363, Free PMC Article 

• GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. CIITA expression is higher when carried by FP single recombinants than when combined with FPgp or FPenv constructs and can induce HLA-DR cell surface expression. However, in-vivo experiments did not show any significant increase in the humoral response. As CIITA already proved to elicit immunogenicity by improving antigen presentation, further in-vivo experiments should be performed to increase the immune responses
2. Therefore, our data identify HIC1 as a novel factor involved in B cell differentiation acting as an epigenetic repressor of CIITA transcription.

PLASMACELLS  IMPORTANT IN  ADAPTIVE IMMUNITIVE

  Differentiation of B lymphocytes into isotope-specific plasma cells represents a hallmark event in adaptive immunity. During B cell maturation, expression of the class II transactivator (CIITA) gene is down-regulated although the underlying epigenetic mechanism is not completely defined. Here we report that hypermethylated in cancer 1 (HIC1) was up-regulated in differentiating B lymphocytes paralleling CIITA repression. Over-expression of HIC1 directly repressed endogenous CIITA transcription in B cells. Reporter assay and chromatin immunoprecipitation (ChIP) assay confirmed that HIC1 bound to the proximal CIITA type III promoter (-545/-113); mutation of a conserved HIC1 site within this region abrogated CIITA trans-repression. More important, depletion of HIC1 with small interfering RNA (siRNA) restored CIITA expression in differentiating B cells. Mechanistically, HIC1 preferentially interacted with and recruited DNMT1 and DNMT3b to the CIITA promoter to synergistically repress CIITA transcription. On the contrary, silencing of DNMT1/DNMT3b or inhibition of DNMT activity with 5-aza-dC attenuated CIITA trans-repression. Therefore, our data identify HIC1 as a novel factor involved in B cell differentiation acting as an epigenetic repressor of CIITA transcription.

1. B. abortus lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1) critical regulatory transcription factor for CIITA induction. 
2. Decreasing CIITA expression in allogeneic MSCs abolished MHC II induction during myogenic differentiation and prevented immunorejection of these cells from the infarcted myocardium, which enhanced beneficial functional effects of MSC implantation on myocardial repair. (2016) 

1. Brazilian Amerindian ancestry compared to Asian, European, and African Genomes.SNPs within or proximal to CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch. SNPs in ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) in the Asian comparison.
2. CLPTM1L and TERT have been implicated in cancers, and CIITA is considered as the "master control factor" for the expression of NPC-associated MHC class II genes. These suggested that both SNPs might be functional. Altogether, our findings expand our understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis.
3. When mouse pDCs and CAL-1 cells were stimulated by GM-CSF, mRNA levels of PU.1, pIII-driven CIITA, total CIITA, MHC class II, and the amount of PU.1 binding to pIII were significantly increased
4. the MHC2TA -168 A/G polymorphism is not associated with susceptibility to rheumatoid arthritis in Caucasians [meta-analysis]
5. Observed no association between the MHC2TA or FCRL3 SNPs and rheumatoid arthritis in Mexican patients.
6. CIITA acts as a general restriction factor against HIV-1 not only in T cells but also in myeloid cells.

  NP_000237.2  MHC class II transactivator isoform 2 

 NP_001273331.1  MHC class II transactivator isoform 1

  NP_001273332.1  MHC class II transactivator isoform 3.