ROG--A NOVEL PROTEIN THAT REGULATES TH2 CYTOKINES

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DESCRIPTION (Adapted from Investigator's Abstract): Dysregulation of helper T (Th) cells immune response is a major pathogenic mechanism mediating several autoimmune and allergic diseases. GATA-3, a zinc finger DNA binding protein, plays an essential role in regulating the development, differentiation, and activation of Th cells. In particular, GATA-3 is expressed only in the Type 2 (Th2) subset where it appears to regulate the production of Th2 cytokines. Thus, altering the function of GATA-3 is a novel approach to manipulate the Th immune response. Previous studies have shown that the function of other GATA family members can be modulated by their interaction with other proteins. Recently, we have isolated a specific GATA-3 interacting protein, that we call ROG (Repressor Of GATA-3), by interaction trap cloning in yeast. ROG is a zinc finger protein that contains a "Broad complex, tramtrack, and bric a brac" (BTB) domain in its N-terminal region. Thus, ROG falls into an expanding family of BTB-containing zinc finger proteins which includes the transcription factor Bcl-6, recently shown to be critical in regulating the Th immune response. ROG is an early response gene in both Type 1 (Th1) and Th2 cells and efficiently represses the activity of both the Interleukin-4 (IL-4) and Interleukin-5 (IL-5) promoters in a GATA-3 specific and GATA-3 dependent fashion in vitro. These findings raise many questions which the experiments in this proposal aim to address. First, what is the mechanism by which ROG represses the function of GATA-3? ROG might prevent GATA-3 from binding to DNA or could form an inactive or inhibitory complex with GATA-3 (Aim 1). Second, the expression of ROG is not limited to Th2 cells suggesting that ROG has functions that are independent of GATA-3. Detailed analysis of the tissue distribution and expression kinetics of ROG, overexpression of ROG in mature Th cells, as well as the generation and characterization of ROG deficient mice should provide important insights into ROG function (Aim 2). For example, ROG might negatively regulate Th1 cytokines or other T cell-specific genes by interacting with a Th1- or T cell-specific transcription factor. Isolation of ROG-interacting proteins as proposed in Aim 3 might identify such novel tissue-specific factors. Finally, the presence of multiple BTB proteins, such as ROG and Bcl-6, capable of repressing Th2 cytokine genes, suggests that ROG might act in concert with other BTB proteins to regulate the differentiation and activation of Th cells by inhibitory mechanisms (Aim 4).