The Hippo pathway regulates photosensitivity in lupus skin.

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.