Laura Cencer
Pronouns: she/her
Research Mentor(s): Joanne Kahlenberg
Research Mentor School/College/Department: Internal Medicine, Division of Rheumatology / Medicine
Program:
Authors: Laura Cencer, Bin Xu, J. Michelle Kahlenberg
Session: Session 4: 1:40 pm – 2:30 pm
Poster: 48
Abstract
Background: Our recent study uncovered that dysregulation, and consequently chronic overactivation, of the hippo signaling pathway in systemic lupus erythematosus (SLE) keratinocytes is driven by overexpression of the WW domain containing protein 1 (WWC1) (1). SLE is characterized by the upregulation of type 1 interferons, which contributes to SLE symptoms such as inflammation and photosensitivity, and is partially driven by the cGAS-STING pathway. This investigation aims to study the role that WWC1 plays in the regulation of type 1 interferon production in keratinocytes through its modulation of the cGAS-STING signaling pathway. Methods: WWC1 stably overexpressing (WWC1OE) or control human N/TERT keratinocytes were or were not primed with IFNa, treated with the STING agonist 2’3’ cyclic GMP-AMP (cGAMP), or transfected with Z-DNA to activate the cGAS-STING pathway. After 6 hours, Western blots were performed to identify the phosphorylation of STING and TANK-binding kinase 1 (TBK1) and RNA-seq was conducted to analyze total downstream gene expression. Additionally, RT-qPCR was performed to analyze the expression of type 1 IFN and interferon stimulated genes (ISGs). Results: Surprisingly, in the context of overexpression of WWC1, cGAMP treatment and Z-DNA transfection resulted in decreased phosphorylation (activation) of TBK1 and STING. This led to the inhibition of downstream type 1 interferons and interferon regulated genes ISG15, and IRF7. Additionally, RNA-seq confirmed that WWC1OE led to the downregulation of type 1 IFN mediated signaling pathways. Conclusion: Our research thus far suggests that the overexpression of WWC1 inhibits type 1 IFN production through modulation of the cGAS-STING pathway in keratinocytes. Future studies will focus on the molecular mechanism underlying how WWC1 regulates cGAS-STING signaling in keratinocytes.
