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

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 small interfering RNA 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. Here, we report early evidence that the keratinocyte sphingolipid and Ca2+ signaling pathways intersect in ATP2A2-controlled ER Ca2+ sequestration, E-cadherin and DP localization, and Ca2+-controlled differentiation, and thus may be important mediators in DD.