Molecular Regulation of CIITA Function by GTP-Binding

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DESCRIPTION (provided by applicant): The induction of class II MHC genes is a central event in the augmentation of immune responses by the anti-tumor cytokine, IFN-gamma. The class II transactivator (CIITA) is a master transcriptional switch for class II MHC, DM, and invariant chain and participates in transcription of class I MHC and beta2-microglobulin genes. CIITA is thus a link between IFN-gamma and the upregulation of genes important for antigen presentation and modulation of immune responses. Defects in CIITA result in a loss of both constitutive and inducible class II MHC expression which leads to a combined loss of T-cell and antibody mediated immunity. CIITA has become the major area of interest in the study of class II MHC gone regulation and is the target of numerous strategies to control class II MHC expression and antigen presentation thereby altering immune responses. Altered regulation of genes involved in antigen processing and presentation is a mechanism by which tumors cells escape immune surveillance and correlates with metastasis in some tumors. The ability to alter class II MHC expression has broad implications not only in tumor biology but in immune responses to infectious agents, autoimmune disease, and transplantation as well. A clear understanding of CIITA function is crucial for devising and implementing strategies aimed at manipulation of immune response genes for tumor immunotherapy. Despite recent advances, our understanding of CIITA's mode-of-action remains limited. CIITA is an unconventional and unique non-DNA binding transcriptional coactivator that utilizes GTP-binding and leucine-rich repeats to deliver a potent activation domain to a broad set of related promoters. Arrival of CIITA in the nucleus commands both promoter accessibility and transcriptional activation. This proposal seeks to elucidate mechanism(s) central to regulating CIITA's function by 1) understanding the role of GTP-binding in regulating CIITA's transactivator function, 2) exploring the contributions of CIITA's C-terminus in regulating transcription, and 3) investigating how CIITA regualtion can be manipulated to impact the expression of the various genes it can influence. This knowledge will help establish a framework that may ultimately lead not only to an accurate view of CIITA's function in transcriptional control, but avenues for improved immunotherapies.