Ceramide synthase 4 controls epidermal lipid composition and barrier function

Ceramide synthases (CerS) are key regulators of ceramides, which are central components of the epidermal lipid barrier. How epidermal lipid homeostasis is controlled and which ceramide synthases are essential for epidermal homeostasis is largely unknown. Previously, we showed that CerS4 controls hair follicle stem cell maintenance. By inactivating CerS4 in mouse epidermis, we now identify CerS4 as a key regulator of epidermal barrier maintenance but not formation. Large scale lipidomics and proteomics showed that loss of CerS4 interferes with epidermal lipid homeostasis resulting in an increase in the amount of key epidermal surface lipids, like cholesterol and -hydroxylated ultra-long chain (ULC)-ceramides. Moreover, loss of CerS4 also increased filaggrin expression as well as processing, which together, lead to acanthosis and hyperkeratosis. Thus, whereas CerS3 controls epidermal barrier formation, CerS4 is central for skin barrier maintenance. In agreement, proteomics revealed a switch from CerS3 to predominantly CerS4 and -5 in adult epidermis. Together, our data show that an imbalance in ceramide synthases alters epidermal lipid homeostasis and drives structural, functional and pathologically relevant skin barrier alterations, thus providing novel insight into lipid associated skin disorders.