CIITA and Its Dual Roles in MHC Gene Transcription

Abstract

Class II transactivator (CIITA) is a transcriptional coactivator that regulates γ-interferon-activated transcription of Major Histocompatibility Complex (MHC) class I and II genes. As such, it plays a critical role in immune responses: CIITA deficiency results in aberrant MHC gene expression and consequently in autoimmune diseases such as Type II bare lymphocyte syndrome. Although CIITA does not bind DNA directly, it regulates MHC transcription in two distinct ways – as a transcriptional activator and as a general transcription factor. As an activator, CIITA nucleates an enhanceosome consisting of the DNA binding transcription factors RFX, cyclic AMP response element binding protein, and NF-Y. As a general transcription factor, CIITA functionally replaces the TFIID component, TAF1. Like TAF1, CIITA possesses acetyltransferase (AT) and kinase activities, both of which contribute to proper transcription of MHC class I and II genes. The substrate specificity and regulation of the CIITA AT and kinase activities also parallel those of TAF1. In addition, CIITA is tightly regulated by its various regulatory domains that undergo phosphorylation and influence its targeted localization. Thus, a complex picture of the mechanisms regulating CIITA function is emerging suggesting that CIITA has dual roles in transcriptional regulation which are summarized in this review.

Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach

“…associated with accessible transcriptionally active chromatin and was predominantly within 2 kb of a gene. The data confirmed some previously identified non-MHC genes such as CD74 and B2M [8,11,19] but also highlighted many additional loci notably after monocytes were treated with IFNγ in which hundreds of additional BIs were revealed compared to the naïve state consistent with previous observations that CIITA-mediated regulation is intimately linked to treatment with interferons [2]. Examples of genes associated with CIITA BIs include key mediators such as STAT1 and STAT3, observed specifically in monocytes treated with IFNγ and B cells, respectively, as well as regions of enrichment for CIITA BIs such as identified within the major histone gene clusters at chromosomes 6p21 and 1q21.…”

Expression and protective role of two novel NACHT-containing proteins in pathogen infection

“…Distinct from NOD proteins, NALP3 is a pyrin domain-containing NLR, and involved in sensing both microbial components and cellular danger signals (Kanneganti et al, 2006;Mariathasan et al, 2006). In addition, some NACHT-containing proteins are known to play roles in stimulating immune responses; for example, NLRC5 is a key regulator of MHC class I-dependent immune responses (Meissner et al, 2010;Kobayashi and van den Elsen, 2012), and CIITA for the master regulator of MHC class II transcription (LeibundGut-Landmann et al, 2004;Devaiah and Singer, 2013).…”

Polycomb Repressive Complex 2 Confers BRG1 Dependency on the CIITA Locus

“…Inactivating mutations in CIITA cause bare lymphocyte syndrome, a lethal immune disorder, and the gene is associated with various other disorders, including cancer (reviewed in Refs. 3,4). CIITA is constitutively expressed in APCs where MHC class I expression is also constitutive, and it can be induced by IFN-g in other cell types.…”