Role of the gender biased transcription factor VGLL3 in promoting autoimmune responses in SLE

PROJECT SUMMARY/ABSTRACT In Systemic Lupus Erythematosus (SLE) women outnumber men in approximately 9:1 ratio. Previously, sexual dimorphism in immune processes has been explained by the location of immune genes on the sex chromosomes, or by the effects of sex hormones. However, as demonstrated by our group, 87.8% of sex-biased genes in skin lie on the autosomes, including interferon (IFN)-response genes (IRGs), as well as other genes associated with autoimmune disease susceptibility, and are unrelated to sex hormone levels in vitro and in vivo. Therefore, the mechanisms involved in autoimmune predisposition in women remain unclear. This application is focused on elucidating the mechanism by which the Hippo pathway regulator Vgll3 promotes autoimmunity, but our previous work identified this factor as a key determinant of sexually dimorphic immune responses. Thus, VGLL3 target genes are enriched for multiple immune response elements associated with multiple autoimmune diseases, including SLE, and a recently developed mouse model, where Vgll3 was expressed constitutively in mouse epidermis develop a robust SLE-like inflammatory phenotype characterized by increased type I IFN activation, and expression of SLE-associated cytokines including Tnfs13b (BAFF), Tnfsf4, type I IFNs, along with robust activation of humoral immune response accompanied by autoantibodies (anti-dsDNA) and immune complex deposition in skin and kidneys. Strikingly, crossing of transgenic Vgll3 mice with Il-7 receptor deficient mice prevented development of this autoimmune phenotype, suggesting a critical role for IL-7 in SLE pathogenesis. These observations form the basis of our hypothesis that VGLL3 nuclear trafficking and modulation of TEAD transcription factor activity promotes an IL-7 dependent autoimmune phenotype. Three aims are proposed to: Elucidate the mechanisms of VGLL3-induced IL7 expression (Aim 1). Determine the dependency of VGLL3 and interferons in promoting sex-biased expression of IL7 (Aim 2), and to determine the mechanism of IL-7-driven systemic autoimmune responses (Aim 3). This proposal will focus on a novel mechanism of sex-biased autoimmunity driven by VGLL3 modulation of Hippo pathway signaling and activation of IL-7, and the target cell type it acts on to drive the down-stream autoimmune response. It will elucidate a novel VGLL3-IL7-autoimmunity pathway in SLE pathogenesis and provide novel approaches for future therapeutic targeting of this devastating disease.