MHC class II transactivator (MHC_II_transact)
Type: Family

Class II transactivator (CIITA) determines the level, cell type specificity, inducibility and extinction of MHC-II expression. CIITA is also the obligatory mediator of INF-gamma inducible MHC-II expression. Thus control of MHC-II expression is ultimately dependent on the control of expression of the CIITA gene itself. Defective CIITA has been shown to be responsible for one class of base lymphocyte syndrome (BLS). BLS is an often fatal genetic defect, characterised by severe immunodeficiency as a result of failure to express MHC class II genes. Expression of CIITA is controlled by four independent CIITA promoters, leading to CIITA transcripts with four distinct first exons. The individual promoters are used in an alternative and tissue-specific manner. CIITA promoter (CIITA-P)I is the promoter used in dentritic cells; CIITA-PII is expressed at insignificant levels and is as yet functionally poorly understood; CIITA-PIII is constitutively expressed in B lymphocytes and can drive CIITA expression after INF-gamma stimulation in a number of different cell types, including endothelial cells and fibroblasts; and CIITA-PIV is the principal INF-gamma-inducible promoter. The cellular and temporal diversity in MHC class II expression is thus regulated via the different usage of the CIITA promoters .

CIITA contains four domains: acidic (A), proline-serine-threonine-rich (PST), GTP-binding (GBD), and leucine-rich repeat (LRR). All of these are required to activate the MHC class II promoter. The acidic transcriptional activation domain interacts with TAFII32. Recruitment of the coactivator protein CBP by the acidic domain has also been shown to lead to synergistic activation of MHC class II promoters and the repression of the interleukin-4 promoter. The PST domain is essential for CIITA function, but its exact role remains unknown. The central region containing the GTP-binding and LXXLL motifs plays an important role in CIITA self-association. This region interacts with itself, the N-terminal domain of CIITA (A/PST) and C-terminal LRR. In addition to their role in CIITA self-association, which is generally necessary for the association of the protein with the import machinery, both GBD (where GTP binding is believed to cause a conformational change compatible with nuclear translocation) and LRR domains have been shown to play important roles in the nuclear localisation of CIITA. Human CIITA appears to contain a NLS. Export of a protein depends on the presence of a specific export signal (NES). NESs are short leucine- rich motifs - in CIITA, they have the consensus LXXXLXXLXL, and are localised in the N- and C-terminal regions .

Numerous in vitro and functional studies have implicated CIITA in multiple steps of the transcriptional activation process: e.g., (i) it may facilitate chromatin remodelling, as it interacts with histone acetyltransferases; moreover, it has intrinsic acetyltransferase activity; (ii) it interacts with the general transcription factors TFIIB, HTAFII32 and HTAFI70, implying that it may recruit the transcriptional apparatus directly; (iii) it interacts with TFIIH and P-TEFb, and may therefore enhance promoter clearance and transcription elongation.