YB-1 DNA-binding protein represses interferon gamma activation of class II major histocompatibility complex genes.

Abstract

SummaryInterferon y (IFN-'r) is the most potent inducer of class II major histocompatibility complex (MHC) genes. This induction is uniquely mediated by three DNA elements in the promoter region of class II MHC genes. One of these DNA elements, Y, contains an inverted CCAAT box. Previously, we have screened a Xgt11 library for Y-binding proteins and identified the YB-1 gene. Here we provide evidence that YB-1 can repress the IFN-3~ induction of class II MHC promoter as well as the Invariant chain (Ii) gene which also contains a Y element in its promoter. This was demonstrated by cotransfecting a YB-1 expression vector with promoter-reporter gene constructs. As an alternate approach, an effcient transient transfection system was developed which resulted in a )70% transfection efficiency. Transfection of YB-1 by this procedure resulted in the near abrogation of IFN-7 induced HLA-DR antigen and mRNA expression. These findings show the functional suppression of class II MHC gene induction by the YB-1 protein.C lass II MHC gene products play a variety of important roles in immune regulation (reviewed in 1-3). These molecules control the acquisition of the mature T cell repertoire and serve as restriction elements for CD4 § T cells. These functions place the regulation of class II MHC antigens as an important topic in immune regulation. The expression of class II MHC genes is primarily regulated at the level of transcription. In the past few years, we and others have delineated an array of cis-acting elements important for optimal class II gene regulation and have identified proteins that bind to these elements. The cis-acting regulatory elements of the DRA gene are probably the best analyzed, and include three elements (S, X, and Y) that are also found in other class II MHC promoters (4-7). The X and Y elements constitute the conserved class II box present in the upstream region of all class II MHC promoters studied to date (8, 9). These two elements are separated by a 19-21-bp spacing that is conserved in length but not in sequence. The Y element contains an inverted CCAAT element, and the X element has been functionally divided into two subregions, X1 and X2, based on the separate interactions of these subregions with the RF-X and hXBP-1 recombinant DNA-binding proteins, respectively (10, 11). The S sequence (also known as H, or W/Z which is a larger DNA sequence) is a heptamer sequence located upstream of the class II box (12-17). These three elements are important for basal gene transcription, and thus far, they are inseparable from elements required for the IFN-T induction of class II MHC genes (12-19).The YB-1 DNA-binding protein was initially identified by using radiolabeled Y element sequence to screen a ~,gt11 expression cDNA library (20). The recombinant YB-1 protein exhibits specificity for the Y element because mutations of an inverted CCAAT sequence in the Y element can abrogate its ability to interact with YB-1. An intriguing feature is the inverse relationship between levels of YB-1 and DRA in IFN-3,-a...

Suppression of grp78 Core Promoter Element-Mediated Stress Induction by the dbpA and dbpB (YB-1) Cold Shock Domain Proteins

“…The mammalian Y-box/CSD proteins regulate a variety of target gene transcriptions. YB-1 has been found to act either as an activator or as a repressor in gene regulation through both in vitro and in vivo studies (4,10,12,13,36,42). Additionally, the Y-box proteins have been shown to bind to single-stranded DNA sequences, damaged DNA, and RNA (5,9,39).…”

“…In mammalian cells, YB-1 can both activate and repress gene transcription (12,13,23,25,36). Interestingly, both dbpA and YB-1 have been shown to repress transcription of major histocompatibility complex (MHC) genes (23,36).…”

“…The Y-box proteins are one of the most evolutionarily related nucleic acid binding proteins defined in bacteria, plants, and animals, characterized by a 70-amino-acid DNA binding domain that is highly conserved with the Escherichia coli cold shock factor CspA (Cs7.4) regulating the cold shock response (38,39). In mammalian cells, YB-1 can both activate and repress gene transcription (12,13,23,25,36). Interestingly, both dbpA and YB-1 have been shown to repress transcription of major histocompatibility complex (MHC) genes (23,36).…”

Retinoic Acid Receptor α Mediates All-trans-retinoic Acid-induced Klf4 Gene Expression by Regulating Klf4 Promoter Activity in Vascular Smooth Muscle Cells

“…It is well known that YB1 belongs to the evolutionarily conserved group of CCAAT-binding proteins that control the expression of a large number of gene products. It classically binds to DNA containing a Y box or inverted CCAAT box (CTGATTGGCCAA) and activates genes associated with proliferation and cancer such as cyclin A, cyclin B1, DNA polymerase ␣, and the multidrug resistance 1 gene (41)(42)(43)(44). Importantly, the present data for the first time provide in vivo and in vitro evidence that YB1 directly binds to the GC box (GGCGGGG) and transactivates the Klf4 promoter in ATRAstimulated VSMCs.…”

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

“…Hnf1 and its transcriptional coactivator, Dcoh, are also involved in the regulation of a number of other genes including some acute-phase inflammatory response genes described above (7,14). Two of the upregulated transcription factors are known to be involved in downregulation of immune and inflammatory responses: nuclease-sensitive element binding protein (Nsep1) represses HLA class II gene expression (65), and glucocorticoid modulatory element binding protein 2 (Gmeb2) modulates transcriptional activity of the glucocorticoid receptor (73). Thus, these transcription factors may mediate immune modulatory effects of ciprofibrate.…”