Regulation of Photosensitivity by the Hippo Pathway in Lupus Skin

Abstract

Objective. Photosensitivity is one of the most common manifestations of systemic lupus erythematosus (SLE), yet its pathogenesis is not well understood. The normal-appearing epidermis of patients with SLE exhibits increased ultraviolet B (UVB)-driven cell death that persists in cell culture. Here, we investigated the role of epigenetic modification and Hippo signaling in enhanced UVB-induced apoptosis seen in SLE keratinocytes.Methods. We analyzed DNA methylation in cultured keratinocytes from SLE patients compared to keratinocytes from healthy controls (n = 6/group). 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 large tumor suppressor kinase 1/2 (LATS1/2) inhibitor (TRULI) and small interfering RNA (siRNA). The interaction between the Yes-associated protein (YAP) and the transcriptional enhancer associate domain (TEAD) was inhibited by overexpression of an N/TERT cell line expressing a tetracycline-inducible green fluorescent protein-tagged protein that inhibits YAP-TEAD binding (TEADi). Apoptosis was assessed using cleaved caspase 3/7 and TUNEL staining.Results. Hippo signaling was the top differentially methylated pathway in SLE versus control keratinocytes. SLE keratinocytes (n = 6) showed significant hypomethylation (Δβ = −0.153) and thus overexpression of the Hippo regulator WWC1 (P = 0.002). WWC1 overexpression increased LATS1/2 kinase activation, leading to YAP cytoplasmic retention and altered proapoptotic transcription in SLE keratinocytes. Accordingly, UVB-mediated apoptosis in keratinocytes could be enhanced by WWC1 overexpression or YAP-TEAD inhibition, mimicking SLE keratinocytes. Importantly, inhibition of LATS1/2 with either the chemical inhibitor TRULI or siRNA effectively eliminated 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.

Serum Metabolomics Analysis of Skin-Involved Systemic Lupus Erythematosus: Association of Anti-SSA Antibodies with Photosensitivity

“…When people with SLE are exposed to UVR, the pathogenic stimulus travels from the skin to the draining lymph nodes through lymphatic vessels and 27 It has been shown that keratinocyte apoptosis caused by altered methylation of Hippo Pathway is correlated with skin photosensitivity in SLE. 28 On the other hand, increased interferon Kappa in keratinocytes improves its sensitivity to UVR exposure and aggravates disease. 29 UVR can induce the type I IFN response to cause the secretion of Th1 associated chemokines such as C-X-C motif chemokine ligand 9/10 in T cells, which contributes to the further recruitment of T cells.…”

HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling

“…SLE patients and healthy controls ( Table S1 ) were recruited from the Taubman Institute Innovative Research Program Personalized Medicine through Integration of Immune Phenotypes in Autoimmune Skin Disease (TIIP-PerMIPA cohort) as described in a previous study. 50 As per the principles of the Declaration of Helsinki, all patients and healthy controls gave written, informed consent before inclusion in the study.…”