Identifying the functional impact of ZNF688 autoantibodies in oral lupus lesions

About This Grant

Abstract Discoid lupus is a form of cutaneous lupus erythematosus (CCLE) that primarily affects the skin, as well as the oral and nasal mucosa. It is a rare condition, with an estimated prevalence of 3-7 cases per 100,000 people in the United States. Lupus erythematosus, including its cutaneous variants, is characterized by the presence of autoantibodies targeting various self-antigens. While autoantibodies that bind to oral epithelial cells have been identified in lupus, their relevance to mucosal discoid lesions and the specific autoantigens involved remain unclear. This proposal responds to the NIH funding announcement PAR25-122, which supports pilot projects investigating understudied proteins associated with rare diseases like discoid lupus. Among the genes high- lighted in this announcement is ZNF688, a transcription factor belonging to the Krüppel-associated box (KRAB)- zinc finger proteins (KZNFs). KZNFs are primarily known to act as transcriptional repressors, regulating critical cellular processes such as proliferation, differentiation, apoptosis, and genome stability. ZNF688 is particularly intriguing for this funding opportunity due to its underexplored nature, with only four publications on the topic available in PubMed. Notably, two of these studies suggest that ZNF688 is a target of autoantibodies in both lupus and another immune-mediated disease, sarcoidosis. Preliminary data have shown high expression levels of ZNF688 in oral epithelial cells, leading to the central hypothesis of this proposal: ZNF688 may regulate oral epithelial cell function, and autoantibodies targeting ZNF688 could contribute to the pathogenesis of oral lesions in discoid lupus. The proposed studies will investigate whether antibodies against ZNF688 affect the differentia- tion or survival of oral epithelial cells. Additionally, the research will identify target genes and pathways regulated by ZNF688, providing insight into how autoantibodies binding this protein may disrupt oral epithelial cell func- tions. The significance of these studies lies in their potential to: (1) Determine whether antibodies targeting ZNF688 influence cell survival or proliferation. (2) Uncover the target genes and pathways regulated by this understudied transcription factor. (3) Shed light on the potential roles of ZNF688 in the pathophysiology of discoid lupus, a rare disease.