PI-5 Regulating Innate immune signaling using single immunoglobulin interleukin-1 regulated receptor protein

Abstract

The Single Immunoglobulin Interleukin-1- related receptor protein (SIGIRR) has been observed to be a negative regulator of the IL-1 (IL-1R) and Toll-like receptor (TLR) signaling pathways. Negative regulation of TLR and IL-1R signaling by SIGIRR is important for innate immune signaling. SIGIRR has been implicated in diseases involving chronic and acute inflammation, including but not limited to asthma, allergies, autoimmunity, and cancer. Based on SIGIRR's ability to negatively regulate IL-1R and TLR signaling, we hypothesize that SIGIRR could be developed as an IL-1 specific therapeutic for IL-1R and TLR receptor antagonism. Using biochemical, biophysical and functional studies, we will determine the molecular mechanism of SIGIRR's negative regulation of IL-1R and Toll-like receptor signaling. Specifically, we will characterize the structure-function relationship of SIGIRR-IL1R and TLR interactions using X-ray crystallography. In support of these studies we have successfully expressed, purified and crystallized a SIGIRR fusion protein. SIGIRR fusion crystals diffract to 2.8 angstrom at the National Synchrotron Light Source II AMX beamline in Brookhaven National Laboratory. We are currently collecting more X-ray diffraction data for determining the structure of the crystallized SIGIRR fusion protein. Future studies include structure determination of SIGIRR protein with IL-1 and Toll-like receptor and development of an IL-1R -SIGIRR based signaling assay. Molecular studies of SIGIRR's negative regulation of IL-1R will aid in our molecular understanding and development effective therapeutic treatment options for regulating IL-1 based inflammation and disease.