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Cited by 38Genetic and rare skin diseases.Skin and Cellular Biology ResearchGenomics and Rare Diseases

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

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Zaver, Shivam A., Sarkar, Mrinal K., Egolf, Shaun, Zou, Jonathan, Tiwaa, Afua, Capell, Brian C., Gudjonsson, Johann E., Simpson, Cory L.·2023·JCI Insight
DOI 10.1172/jci.insight.170739PMC PMC10561730

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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.

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  • MEK inhibition was shown as a potential targeted therapy strategy for Darier disease in a SERCA2-deficient HEE model.

    “Building upon the SERCA2-deficient HEE model, Mitogen activated protein kinase kinase (MEK) inhibition was shown as a potential targeted therapy strategy for DD [30].”

    From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [30]

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Authors
Zaver, S. A., Sarkar, M. K., Egolf, S., Zou, J., Tiwaa, A., Capell, B. C., Gudjonsson, J. E., & Simpson, C. L.
Affiliations
  • University of Washington (US)
  • University of Michigan (US)
  • University of Pennsylvania (US)
Corresponding author
Simpson, Cory L.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2023-09-22
Volume
8
Issue
18
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.170739
PMC
PMC10561730
OpenAlex
W4385740688
Cited by
38
References
2
Citations by year
2026: 16 · 2025: 10 · 2024: 11 · 2023: 1
FWCI
6.31
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (P30-AR075043,R21-AR077741,T32-AR007465,F99-CA264315,R01-AR07761,P30-AR069589,K08-AR075846)
  • National Psoriasis Foundation (852098)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
Darier disease, SERCA2, MEK inhibitors, keratinocyte adhesion, keratinocyte differentiation, desmosomes, MAPK signaling, haploinsufficiency, skin blistering, targeted therapy

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