Class II Transactivator: Mastering the Art of Major Histocompatibility Complex Expression
Creators: name: Ting, J. P.-Y.
name: Harton, J. A.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2000

description: Great progress in understanding the relative importance of various portions of CIITA for transcriptional activation of class II MHC genes has been made since CIITA's discovery in 1993. Emerging from these studies is a fairly consistent picture where CIITA is expressed, binds GTP, translocates to the nucleus, and interacts with specific DNA-binding transcription factors and basal transcription components, thus opening and activating class II MHC and related promoters. Despite these strides, this model is essentially unchanged from that initially espoused. The observation that class II MHC promoters in some B cells are bound to X and Y box binding proteins and thus open even in the absence of CIITA, whereas these same promoters in non-B cells are closed until CIITA is present, is provocative. One potential explanation is that CIITA possesses two distinct functions, the ability to direct the opening of responsive promoters (presumably through some form of remodeling) and the ability to activate transcription through its activation domain and protein-protein interactions (132, 141). The presence of a locus control region responsive to a B-cell-specific factor is another possibility, yet CIITA must, in some fashion, be directing chromatin remodeling in cells which can be induced to express CIITA. While CBP is an obvious candidate for mediating remodeling, no conclusive experiments have shown that CBP is required for the remodeling of class II MHC promoters. The studies above support interactions between CIITA and transcription factors, but does CIITA merely bind these factors to place the activation domain appropriately? Why has it been difficult to demonstrate a role for CIITA in a transcription complex? Is GTP binding only essential for nuclear import? Is nuclear export of CIITA occurring and is it relevant? What aspect of class II MHC transcription requires that retinoblastoma protein Rb be present? Is CIITA a prototype for a family of transcriptional coactivators? Why is limited class II expression observed in the absence of CIITA? The evolutionary conservation of W-, X-, and Y-containing promoters in mammals, birds (104), amphibians (51), and fish (121) suggests that CIITA may be extremely old; what are its origins? All remaining questions aside, CIITA is truly a remarkable protein. Controlled by up to four separate promoters, CIITA has been imparted a complex pattern of inducible and constitutive expression that can be regulated in developmental pathways. Through exercising specific control over the transcription of every major component of class II MHC antigen presentation pathway, CIITA gains the title of a master regulator. As CIITA appears to be class II MHC specific, it can be thought of as the core transcription factor of which all the remaining components are but cofactors. This is central to the concept of CIITA as a scaffolding protein or integrator and perhaps alters our view of transcriptional control away from promoters and individual factors towards a more unified enhanceosome perspective. The view of CIITA as a master regulator has implications for practical applications that are staggering. Successful engineering of dominant-negative CIITAs may lead to the production of transplant tissues unable to express class II MHC and the associated self peptides which contribute so significantly to graft rejection. A thorough understanding of CIITA's molecular mechanisms may lead to therapeutics which allow temporary enhancement or suppression of class II MHC, thus favorably altering the immune response during critical events in pathogenesis, autoimmune disease, tumorigenesis, and neuroinflammation.