TOWARDS UNDERSTANDING THE NON-CLASSICAL SECRETION OF HUMAN INTERLEUKIN-1 ALPHA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Interleukins (IL's) are involved in a wide spectrum of biological processes associated with infection, inflammation, and autoimmunity. IL-1's in particular are pro-inflammatory cytokines, and they assist the host in fighting infection. Deficiency in IL-1's is known to result in lethality in bacterial infections. In addition, recent studies suggest that IL-1¿ also plays a role in wound healing, carcinogenesis, tumor invasion, rheumatoid arthritis, and Alzheimer's disease. IL-1¿ lacks the N-terminal signal peptide, therefore, unlike most other extracellular proteins, it is not secreted through the classical endoplasmic recticulum  Golgi pathway. Preliminary studies have suggested that the release of IL-1¿ into the extracellular compartment occurs by the formation of a multi-protein complex to the calcium- binding protein, S100A13 in the presence of copper. Although useful information exists on the IL-1 signaling process, the exact mechanism of IL-1¿ secretion into the extracellular compartment is not clear. Until now structure- function data have been limited for IL-1¿ because of the difficulty in its overexpression in mammalian cells. In this context, the purpose of the proposed research is to fully understand IL-1¿'s non-classical release and it's binding to copper and S100A13. Specific aims of this proposal include: 1) determing the binding affinity of IL-1¿ for copper and S100A13; 2) characterizing the molecular interactions necessary for the non-classical secretion of IL-1¿. A complete understanding of the non-classical secretion of IL-1¿ will provide valuable information towards understanding the general principles of export of proteins without signal peptide. Furthermore, over the funding period, this project will engage numerous undergraduates and master's level graduate students in independent research, enhancing their learning of scientific principles, giving them an opportunity to make unique contributions to the study the role played by IL-1¿ in this devastating family of diseases, and stimulating their excitement for future careers in biomedical research. Moreover, the funding of this application will expand student research in protein stability, structure and function and enable more students from Kentucky, a state traditionally underrepresented in biomedical sciences, to successfully advance into biomedical graduate programs.