{"doi":"10.1002/art.42460","title":"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.","journal":"Arthritis & Rheumatology","year":2023,"id":335032,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":237109,"name":"Patrick Coit","orcid":"0000-0003-0660-764X","position":1,"is_corresponding":false},{"id":1064002,"name":"Bin Xu","orcid":"0000-0002-0423-925X","position":2,"is_corresponding":false},{"id":406738,"name":"Amanda Victory","orcid":"0000-0002-4948-5702","position":3,"is_corresponding":false},{"id":353207,"name":"Mehrnaz Gharaee‐Kermani","orcid":"0000-0002-2177-2427","position":4,"is_corresponding":false},{"id":354707,"name":"Shannon N. Estadt","orcid":null,"position":5,"is_corresponding":false},{"id":674982,"name":"Mitra P. Maz","orcid":"0000-0002-2359-0862","position":6,"is_corresponding":false},{"id":880242,"name":"Jacob William Shelton Martens","orcid":null,"position":7,"is_corresponding":false},{"id":252613,"name":"Rachael Wasikowski","orcid":null,"position":8,"is_corresponding":false},{"id":652104,"name":"Craig J. Dobry","orcid":"0000-0002-1468-1156","position":9,"is_corresponding":false},{"id":12819,"name":"Lam C. Tsoi","orcid":"0000-0003-1627-5722","position":10,"is_corresponding":false},{"id":262760,"name":"Ramiro Iglesias‐Bartolomé","orcid":"0000-0002-0792-1254","position":11,"is_corresponding":false},{"id":249277,"name":"Céline C. Berthier","orcid":"0000-0003-3539-1075","position":12,"is_corresponding":false},{"id":233179,"name":"Allison C. Billi","orcid":"0000-0001-7115-9113","position":13,"is_corresponding":false},{"id":12829,"name":"Jóhann E. Guðjónsson","orcid":"0000-0002-0080-0812","position":14,"is_corresponding":false},{"id":235896,"name":"Amr H. Sawalha","orcid":"0000-0002-3884-962X","position":15,"is_corresponding":false},{"id":233184,"name":"J. Michelle Kahlenberg","orcid":"0000-0002-4006-8945","position":16,"is_corresponding":false},{"id":353208,"name":"Grace A. Hile","orcid":"0000-0002-3629-8633","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T01:09:53.742667Z","pmid":"36704840","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}