031 Enhancement of Th2 cell differentiation by TRIM32 deficiency is negatively associated with PKCζ

Abstract

Autoimmune disease is the leading cause of morbidity among women. For largely unknown reasons, many autoimmune diseases show a striking female bias. Fibrosis is a common feature of female-biased autoimmune diseases. This is exemplified by systemic sclerosis (SSc), a debilitating disease marked by progressive skin hardening and organ damage that affects women at ninefold the rate of men. We previously identified the transcriptional cofactor VGLL3 as an immune regulator enriched in female skin whose targets overlap significantly with genes dysregulated in SSc. We further showed that excess epidermal VGLL3 causes cutaneous and systemic autoimmune disease in mice. However, how VGLL3 promotes autoimmunity in the skin remains entirely unexplored. By combining IP-mass spectrometry, RNA-seq, and ChIP-seq approaches in cell culture and transgenic mice with epidermal VGLL3 overexpression, we have found that VGLL3 binds key factors in the Hippo signaling pathway to modulate both immune genes and established Hippo pathway targets. These targets include the pro-fibrotic factor CTGF and members of the TGF-b pathway, both of which have been implicated in SSc pathogenesis. Consistent with this, transgenic mice with epidermal VGLL3 overexpression show gross and microscopic features of skin fibrosis. These findings elucidate the molecular mechanisms by which VGLL3 promotes autoimmunity and leads to the hallmark fibrosis of many autoimmune diseases such as SSc. Furthermore, this reveals a previously unexplored connection between autoimmune disease and the Hippo signaling pathway, which has recently been linked to organ fibrosis.