Activation of the immune system is important for the survival of an organism however the response to a variety of environmental factors such as pathogens must be properly regulated. An important protein involved in this regulation is a master regulatory protein known as the class II transactivator (CIITA). Upon infection, CIITA acts to induce the expression of a particular subset of genes, thereby activating the immune system and leading to a vigorous effort by the body to combat the pathogen. Individuals with mutations in CIITA do not exhibit a normal immune response and ultimately leads to death in early childhood due to common infections. Despite its prominent role in triggering an immune response, the cellular mechanisms that control CIITA activity are not well understood. One mechanism being explored is the role of addition or subtraction of phosphate on CIITA function. CIITA present in the nucleus of cells is phosphorylated, which correlates with its inability to induce the expression of immune system genes. CIITA is also exported out of the nucleus into the cytoplasm of cells, although the rationale for this export remains to be determined. One hypothesis is that phosphorylation of nuclear CIITA specifically causes it to interact with proteins that drive CIITA out of the nucleus, thereby shutting down CIITA-regulated expression of immune system genes. This may allow the organism to rapidly and precisely control the extent of CIITA activity and therefore mediate the magnitude of an immune response. Preliminary results identified several proteins that potentially interact with CIITA, which may be specifically involved in phosphorylating CIITA and controlling its cytoplasmic/nuclear localization, thereby playing a critical role in regulating CIITA function. However, the means by which these proteins interact with CIITA as well as their specific mechanisms of controlling CIITA activity within a cell have yet to be identified. This project examines the ability of these proteins to interact with CIITA, modify its structure, alter its location in the cell, and regulate its function in initiating the expression of immune system genes. Understanding the cellular and molecular mechanisms that control CIITA activity will be crucial to devising strategies to manipulate the immune system and alter immune responses. Broader Impacts: This project seeks to further develop the first active, on-going laboratory research program at the college, providing an opportunity for undergraduate students to participate in the project and gain valuable experience and exposure to molecular biology research design, methodology, data collection and results interpretation. During the three-year timeframe of this project, undergraduate students will be intimately involved in the program as summer or academic year interns. Furthermore, this project will form the basis for the addition of experimental research courses to the biology curriculum, expanding opportunities for students to gain laboratory experience within the framework of their studies. By bringing together students and faculty and providing opportunities to participate in molecular biology research, this project will establish the foundation for further curricular development and strengthen undergraduate scientific training at Sarah Lawrence College.
