The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

Abstract

In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein–protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.

EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes

“…Since the entire cluster of HLA II genes were down regulated by EBNA2, we suspected that these effects are mediated through the master transcriptional regulator of HLA-II CIITA [ 40 ]. Analysis of published ChIP-seq data revealed that EBNA2 and CIITA both bound to numerous sites across the HLA-class II region ( Fig 4A ).…”

“…CIITA was identified as a transcriptional coactivator essential for expression of HLA-class II genes. Its expression correlates tightly with HLA-II gene transcription, and is mostly restricted to lymphoid cells [ 40 ]. CIITA is known to be regulated through multiple cell-type specific promoter and distal enhancers that make a network of contacts with each promoter [ 40 , 49 ].…”

“…Here, we show that EBV primary infection of B-lymphocytes results in a concerted down regulation of HLA II genes. We show that EBNA2 is sufficient to down regulation the HLA class II genes, and that this could be attributed largely to a down regulation of the master transcriptional regulator of HLA-class II CIITA [ 40 ]. EBNA2 binds to several regions near the CIITA gene, and we show that EBNA2 binding and activation of a neighboring gene correlates with inhibition of CIITA.…”

Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

“…The NLRA subfamily comprises of a sole member, namely: the Class II Major Histocompatibility Complex Transactivator (CIITA), which contains an N -terminal acidic transactivation domain, but also a CARD domain, a nuclear localization signal and four LRRs [ 16 ]. CIITA has been recognized as the “master regulator” of Major Histocompatibility Complex (MHC) class II molecule (MHC-II) expression since it controls the differential expression of MHC-II genes [ 17 ].…”

“…In mice and humans, CIITA expression is regulated by three and four distinct promoters, respectively, resulting in different isotypes [ 16 , 22 ]. Human keratinocytes mainly express type IV CIITA transcribed from promoter IV upon IFN-γ stimulation [ 22 ], which can be further induced by interleukin (IL)-18 [ 27 ], which subsequently leads to MHC-II expression [ 22 ].…”