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.
Highlights
Département de Biologie, Université de Sherbrooke, 2500 Boul., Sherbrooke, QC J1K 2R1, Canada; Citation: León Machado, J.A.; 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
The study of a rare severe combined primary immunodeficiency called the bare lymphocyte syndrome (BLS) led to the identification of class II transactivator (CIITA) and of the three genes coding for the subunits of the heterotrimeric RFX complex binding to the X-box in the highly conserved W/SXY module found in all MHC-II gene promoters
Bruchez and colleagues showed that CIITA inhibited the Ebola virus and coronaviruses, CIITA was acting in this instance as a conventional MHC-II gene activator and not as a viral restriction factor [157]
Summary
The major histocompatibility complex (MHC; in humans, human leukocyte antigen, HLA) class I and class II molecules are antigen-presenting molecules for CD8+, and CD4+ T cells, respectively, and are of crucial importance for the cellular immune response Their expression is mainly controlled at the level of gene transcription. This conundrum was resolved when it was recognized homolog of CIITA, NLRC5, functions as conditions. Deletion of the acidic and P/S/T domains leads to an exclusively cytoplasmic CIITA fragment (L335), which can, be driven very efficiently to an exclusively nuclear localization by the addition of an SV40 large T nuclear localization signal (NLS-L335) Both NLS-L335 and L335 are strongly dominant-negative, suggesting that essential interactions with protein partners can occur both in the nucleus and in the cytoplasm [31,34]. Mono-ubiquitination was shown to increase CIITA-dependent MHC-II transactivation in a non-degradative manner [37]
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