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

• Published in: International journal of molecular sciences Vol. 22; no. 3; p. 1074
• Main Authors: León Machado, Jorge Alfonso, Steimle, Viktor
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.01.2021; MDPI
• Subjects: Amino acids; Animals; Antigens; Binding; Caspase; CIITA; CIITA protein; Combinatorial analysis; COVID-19 - genetics; COVID-19 - metabolism; Deoxyribonucleic acid; DNA; Ebolavirus - physiology; Gene expression; Gene Expression Regulation; Gene regulation; Genes, MHC Class II; Hemorrhagic Fever, Ebola - genetics; Hemorrhagic Fever, Ebola - metabolism; Homology; Humans; Kinases; Leucine; Major histocompatibility complex; MHC genes; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Nlr protein; NLR Proteins - genetics; NLR Proteins - metabolism; NLRC5; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleotides; Phosphorylation; Protein interaction; Protein Interaction Maps; Proteins; Review; RNA polymerase; SARS-CoV-2 - physiology; Severe acute respiratory syndrome coronavirus 2; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription; Virus Replication; NLRC5; CIITA; gene regulation; MHC genes
• DOI: 10.3390/ijms22031074
• ISSN: 1422-0067; 1661-6596

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.