The Hippo pathway regulates photosensitivity in lupus skin.

26 Jan 2023
Hile GA, Coit P, Xu B, Victory AM, Gharaee-Kermani M, Estadt SN, Maz MP, Martens JWS, Wasikowski R, Dobry C, Tsoi LC, Iglesias-Bartolome R, Berthier CC, Billi AC, Gudjonsson JE, Sawalha AH, Kahlenberg JM


Photosensitivity is one of the most common manifestations of systemic lupus erythematosus (SLE), yet its pathogenesis is not well understood. Normal-appearing epidermis of patients with SLE exhibits increased UVB-driven cell death that persists in cell culture. Here we investigate the role of epigenetic modification and Hippo signaling in enhanced UVB-induced apoptosis seen in SLE keratinocytes.


DNA methylation was analyzed using bisulfite sequencing from cultured SLE keratinocytes compared to healthy control (n=6, each). Protein expression was validated in cultured keratinocytes using immunoblotting and immunofluorescence. An immortalized keratinocyte line overexpressing WWC1 was generated via lentiviral vector. WWC1-driven changes were inhibited using a LATS1/2 inhibitor (TRULI) and siRNA. YAP-TEAD interaction was inhibited via overexpression of TEADi protein. Apoptosis was assessed using cl-caspase 3/7 and TUNEL staining.


Hippo signaling is the top differentially methylated pathway in SLE versus control keratinocytes. SLE keratinocytes show significant hypomethylation (Δβ = -0.153) and thus overexpression of the Hippo regulator WWC1 (p=0.002, n=6). WWC1 overexpression increases LATS1/2 kinase activation, leading to YAP cytoplasmic retention and altered pro-apoptotic transcription in SLE keratinocytes. Accordingly, UVB-mediated apoptosis in keratinocytes can be enhanced by WWC1 overexpression or YAP-TEAD inhibition, mimicking SLE keratinocytes. Importantly, chemical and siRNA-mediated LATS1/2 inhibition effectively eliminates enhanced UVB-apoptosis in SLE keratinocytes.


Our work unravels a novel driver of photosensitivity in SLE: overactive Hippo signaling in SLE keratinocytes restricts YAP transcriptional activity, leading to shifts that promote UVB-apoptosis.