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Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease
Shivam A. Zaver, … , Johann E. Gudjonsson, Cory L. Simpson
Shivam A. Zaver, … , Johann E. Gudjonsson, Cory L. Simpson
Published August 10, 2023
Citation Information: JCI Insight. 2023;8(18):e170739. https://doi.org/10.1172/jci.insight.170739.
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Research Article Dermatology Article has an altmetric score of 10

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

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Abstract

Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than 2 decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2-knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed RNA sequencing and proteomics analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAPK signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings, with lesions showing keratin deficiency, cadherin mislocalization, and ERK hyperphosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multiomic analysis with human organotypic epidermis as a preclinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified MEK inhibition as a treatment strategy for Darier disease.

Authors

Shivam A. Zaver, Mrinal K. Sarkar, Shaun Egolf, Jonathan Zou, Afua Tiwaa, Brian C. Capell, Johann E. Gudjonsson, Cory L. Simpson

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Figure 2

Keratinocytes lacking SERCA2 exhibit transcriptomic alterations in mediators of epidermal adhesion and differentiation.

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Keratinocytes lacking SERCA2 exhibit transcriptomic alterations in media...
(A) Results from bulk RNA sequencing of SERCA2 HET versus control cells. Volcano plot depicts log2 fold-changes of genes significantly downregulated (blue) and upregulated (red) with cutoff (dashed line) 0.05 for adjusted P value. (B) Gene ontology (GO) analysis of transcripts significantly altered (adjusted P ≤ 0.05) in HET cells revealed upregulation (red) in genes controlling ER stress and growth factor signaling and downregulation (blue) of genes controlling epidermal differentiation and antiviral response. (C) Control (+/+), HET (+/-), or KO (-/-) THEKs were differentiated in E-medium for 24 hours, and mRNA transcripts were quantified by reverse transcription quantitative PCR (RT-qPCR). Graphs display mean ± SD with plotted values from N = 4 biological replicates; P values from 1-way ANOVA with Dunnett’s adjustment for multiple comparisons. DSG1, desmoglein 1; KRT, keratin.

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