Mutation of the HSR-domain of Aire disrupts binding to a novel interacting protein

Autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED), a rare autoimmune disease, is caused by defects in the autoimmune regulator (AIRE) gene. Aire is a transcriptional regulator that directs the expression of tissue-specific antigens (TSAs) in the thymus, therefore supporting the elimination of self-reactive thymocytes during negative selection. Although Aire plays a critical role in the prevention of autoimmune disease, the molecular mechanism of Aire function is not well understood. Our lab has identified two novel Aire interacting proteins. These proteins form a complex that facilitates gene repression. We hypothesize that Aire interacts with these proteins to disrupt the ability of this complex to silence genes and thus induce the expression of TSA genes in medullary thymic epithelial cells (mTECs). In this study, we investigated the interaction of one of these novel interacting proteins with Aire mutants using coimmunoprecipitation. We determined that this protein binds to the HSR-domain of Aire. Interestingly, the disease causing mutant, Y85C, disrupts this binding. These results suggest that this interaction may be functionally important in Aire regulation of TSA expression.