Site α Is Crucial for Two Routes of IFNγ-Induced MHC Class I Transactivation: The ISRE-Mediated Route and a Novel Pathway Involving CIITA

Abstract

The constitutive and cytokine-induced levels of major histocompatibility (MHC) class I expression are tightly controlled at the transcriptional level. In this study, it is shown that the cis-acting regulatory element site alpha of the MHC class I promoter is essential for the IFN gamma-induced transactivation of MHC class I gene expression through the ISRE. Moreover, it was discovered that the class II transactivator (CIITA), which is itself under the control of the IFN gamma induction pathway, strongly transactivates MHC class I gene expression and exerts its activity through site alpha. Therefore, site alpha is a crucial regulatory element, mediating the classic route of IFN gamma induction via the ISRE as well as a novel route of MHC class I transactivation involving CIITA.

A T Lymphocyte-Specific Transcription Complex Containing RUNX1 Activates MHC Class I Expression

“…Under these conditions, LEF1 and RUNX1 together activated the class I promoter 7.3-fold. CIITA alone enhances class I promoter activity 6.6-fold, as we and others have demonstrated previously (16,20,21). However, in the presence of both LEF1 and RUNX1, CIITA dramatically increased promoter activity to 40.2-fold, suggesting that CIITA and the T cell enhanceosome act synergistically.…”

“…The CRE, located between Ϫ100 and Ϫ107 bp, is known to interact with members of the ATF/CREB family and has been shown to both positively and negatively regulate MHC class I transcription (6,16,(71)(72)(73)(74)(75)(76). Activation by CIITA, the IFN-␥ mediator and B cell coactivator, depends on the CRE element: deletion of the CRE eliminates activation of the class I promoter by IFN-␥ (16,20,21). Therefore, we considered the possibility that the class I CRE element participated in T cell, as well as B cell, enhanceosome function.…”

“…High class I expression in B lymphocytes is mediated by series of promoter proximal elements, located between Ϫ68 and Ϫ500 bp. These elements include enhancer A (8 -13), IFN-␥-stimulated response element (14 -19), and a composite RFX/cAMP response element (CRE) 2 (16,20,21). These same elements are also the targets of hormone/cytokine signals (6).…”

“…For example, a B lymphocyte-specific enhanceosome consisting of the coactivator CIITA and DNA-bound transcription factors RFX, CREB/ATF, and NF-Y leads to high cell surface class I and II expression in B lymphocytes (22)(23)(24)(25). CIITA, a transcriptional coactivator that induces both MHC class I and class II genes does not bind DNA directly, but rather depends on factors, such as RFX and CREB/ ATF, that bind to the CRE element (16,20,21). The constitutively high level of expression of MHC class I in B lymphocytes is due, in part, to the presence of a CIITA enhanceosome complex that maintains high transcription rates of class I genes.…”

Revisiting the specificity of the MHC class II transactivator CIITA in vivo

“…This was explained by the finding that the MHC-II-specific regulatory machinery, including CIITA, contributes to optimal expression of MHC-I genes [6,7]. This again did not constitute a major challenge to the conclusion that CIITA is specific for MHC-II and related genes.…”