IRF5-TNPO3 locus: Inclusion of TNPO3 as a unique regulator of IRF5 expression an

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DESCRIPTION (provided by applicant): Project Summary The NIH estimates up to 23.5 million Americans suffer from autoimmune diseases and that the prevalence is rising; this statistic is higher than the number of Americans having cancer (9 million) or heart disease (22 million). Systemic lupus erythematosus (SLE) is the third most frequent autoimmune disease affecting approximately 1 in 2000 people. It is the prototype of complex autoimmune diseases and is characterized by extreme breakdown of self-tolerance resulting in multiple immunologic abnormalities. Cures are not yet available for SLE and patients face a lifetime of illness and treatment. Given the clinical heterogeneity of this disease, combined with limited knowledge of pathogenesis, designing new treatment options has been difficult. Recent findings from joint linkage and genome-wide association studies (GWAS) have provided significant insight into the genes and pathways contributing to disease pathogenesis. SLE is highly heritable with a strong genetic component that includes the interferon regulatory factor 5 (IRF5)-transportin 3 (TNPO3) region. Genetic variants in the IRF5-TNPO3 locus have been associated with SLE risk in every published study testing this region and in every ethnic population. Although some effort has recently gone into studying the functional consequence of genetic variants in IRF5, few studies have included an analysis of TNPO3 expression and function in SLE. The primary goal of this research proposal is to determine how the IRF5-TNPO3 locus alters SLE disease risk by experimentally bridging the gap(s) in knowledge between identification of this causal locus and its actual functional influence on SLE risk. IRF5 encodes a transcription factor central to the innate and adaptive immune response through its regulation of key processes including cytokine production, chemokine and chemokine receptor expression, and autoantibody production. TNPO3 is a member of the importin family and encodes a nuclear import receptor that mediates nuclear entry of serine/arginine (SR)-rich proteins such as splicing factors SFRS1 and SFRS2. Based on recent experimental findings from our lab, we hypothesize that the genetic risk coming from the IRF5-TNPO3 locus is not solely from IRF5 and directly involves TNPO3 function via its ability to regulate novel mechanisms controlling IRF5 alternative splicing and nuclear localization. This hypothesis will be tested in the following Specific Aims: 1) Determine the level of IRF5 and TNPO3 transcript and protein expression in immune cells from healthy donors and SLE patients carrying the risk and non-risk haplotypes at IRF5-TNPO3 SNPs, 2) Determine whether TNPO3 controls IRF5 transcript expression through its ability to regulate the import of SR proteins to the nucleus, and 3) Determine whether IRF5, TNPO3 and NUP62 differentially interact in genotyped healthy donor and SLE immune cells resulting in altered IRF5 nuclear localization. Results from this study will bridge the gap between disease- associated genetic variation, gene expression, protein function, and disease phenotype, and identify novel mechanisms that can be therapeutically targeted to regulate IRF5 expression and activation in SLE.