SERCA2-Controlled Ca2+-Dependent Keratinocyte Adhesion and Differentiation Is Mediated via the Sphingolipid Pathway: A Therapeutic Target for Darier's Disease

Abstract

Summary Darier’s Disease (DD), caused by mutations in the endoplasmic reticulum (ER) Ca2+ ATPase ATP2A2 (SERCA2b), is a skin disease that exhibits impaired epidermal cell-to-cell adhesion and altered differentiation. Although previous studies have shown that keratinocyte Ca2+ sequestration and fluxes are controlled by sphingolipid signaling, the role of this signaling pathway in DD previously has not been investigated. We show here that sphingosine levels increase and sphingosine kinase (SPHK1) expression decreases after inactivating SERCA2b with the specific SERCA2 inhibitors thapsigargin (TG) or siRNA to SERCA2b. Conversely, inhibiting sphingosine lyase rescues the defects in keratinocyte differentiation, E-cadherin localization, Desmoplakin (DP) translocation, and ER Ca2+ sequestration seen in TG-treated keratinocytes. To our knowledge, it was previously unreported that the keratinocyte sphingolipid and Ca2+ signaling pathways intersect in ATP2A2- controlled ER Ca2+ sequestration, E-cadherin and desmoplakin localization and Ca2+ - controlled differentiation, and thus may be important mediators in DD.

Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis

“…Recently, S1P has been shown to have signaling properties that regulate keratinocyte cell function (31)(32)(33)(34)(35)(36). Here, we report that the deletion of Sgpp1, the gene encoding SPP1, greatly disturbs epidermal homeostasis in mice.…”

“…S1P has long been known to induce elevations of intracellular Ca 2ϩ levels through the release from internal stores (5, 6), and its metabolism is believed to serve as a complementary Ca 2ϩ signaling pathway to promote keratinocyte differentiation (31). Elevating S1P levels through sphingosine kinase activation or lowering S1P lyase levels has been shown to increase Ca 2ϩ levels and promote differentiation (33,34). Furthermore, the up-regulation of alkaline and acid ceramidases (see scheme in Fig.…”

“…Sgpp1 Deletion Increases Ca 2ϩ Levels within the Epidermis-S1P has been shown to induce differentiation in keratinocytes by controlling intracellular Ca 2ϩ levels (6,32,33,34,53). To determine whether epidermal Ca 2ϩ was increased in vivo by the Sgpp1 deletion, Calcium Green-1, which exhibits a fluores- groups, using a cutoff of p Ͻ 0.05 and a fold change of greater than 2.…”

Fructose 1, 6‐diphosphate regulates desmosomal proteins and collagen fibres in human skin equivalents

“…2e). We further demonstrated that the mRNA expression level of SERCA2, which is responsible for Ca 2+ uptake in the keratinocytes (26,27), was significantly down-regulated, indicating that the amount of Ca 2+ in the endoplasmic reticulum may be reduced by FDP.…”

Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

“…Impaired adhesion, a feature of the disease, is likely to result from changes in DSP traffi cking (Celli et al, 2012;Dhitavat et al, 2003;Hobbs et al, 2011). The desmosomal proteins DSP, DSG3 and DSC3 appeared disorganised with a thicker and punctuated distribution under the plasma membrane, while DSG3 and DSC3 also presented perinuclear staining, suggesting that they had been retained in the endoplasmic reticulum (ER).…”