| Description: |
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 controlof MHC-II expression is ultimately dependent on the control of expressionof the CIITA gene itself. Defective CIITA has been shown to be responsiblefor 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 byfour independent CIITA promoters, leading to CIITA transcripts with four distinct first exons. The individual promoters are used in an alternativeand tissue-specific manner. CIITA promoter (CIITA-P)I is the promoter usedin dentritic cells; CIITA-PII is expressed at insignificant levels and is as yet functionally poorly understood; CIITA-PIII is constitutivelyexpressed in B lymphocytes and can drive CIITA expression after INF-gammastimulation in a number of different cell types, including endothelial cellsand 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 requiredto activate the MHC class II promoter. The acidic transcriptional activationdomain interacts with TAFII32. Recruitment of the coactivator protein CBP bythe acidic domain has also been shown to lead to synergistic activation ofMHC class II promoters and the repression of the interleukin-4 promoter. ThePST 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, bothGBD (where GTP binding is believed to cause a conformational change compatible with nuclear translocation) and LRR domains have been shown toplay 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 arelocalised in the N- and C-terminal regions[, , ].Numerous in vitro and functional studies have implicated CIITA in multiplesteps of the transcriptional activation process: e.g., (i) it may facilitatechromatin remodelling, as it interacts with histone acetyltransferases;moreover, it has intrinsic acetyltransferase activity; (ii) it interactswith the general transcription factors TFIIB, HTAFII32 and HTAFI70, implyingthat it may recruit the transcriptional apparatus directly; (iii) itinteracts with TFIIH and P-TEFb, and may therefore enhance promoterclearance and transcription elongation. |
