Functions of the AP-1 transcription factor Fra-2 in epidermal development and disease

Resumen

Altered epidermal differentiation and the production of inflammatory cytokines and chemokines by epidermal cells are hallmarks of numerous skin diseases affecting over 25% of the human population. Here I have identified Fra-2, an AP-1 transcription factor, as a key regulator of terminal epidermal differentiation and cytokine expression in keratinocytes. Mechanistically, Fra-2 binds and transcriptionally regulates gene promoters of epidermal differentiation genes, located within the Epidermal Differentiation Complex (EDC). EDC gene promoters are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in non-differentiated keratinocytes, where it was found mono- and dimethylated on lysine 104, and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on serine 320 and threonine 322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation. During skin morphogenesis in mice, epithelial-restricted, ectopic expression of Fra-2 induced EDC gene expression. Moreover, in a papilloma-prone background, reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Besides impairing keratinocyte differentiation, loss of epidermal Fra-2 (Fra-2Dep) results in inflammation characterized by epidermal hyperplasia, infiltration of inflammatory cells into the dermis and epidermis and high serum cytokine levels. Additionally, Fra-2-deficient keratinocytes display increased p65/NF-kB activity and the concurrent removal of epithelial p65 partially attenuates the skin and systemic phenotype of Fra-2Dep mutants. These findings identify an important function of epidermal p65 in initiating inflammatory processes. Additionally, a cell autonomous but indirect regulation of Fra-2 on the expression of the cytokine TSLP by keratinocytes was uncovered. Interestingly, transplanting Fra-2Dep skin onto immune-compromised SCID mice gave rise to the formation of skin papillomas, suggesting a tumor protective role of the acute inflammatory response observed in Fra-2Dep skin. My data demonstrate a cell-autonomous function of Fra-2 in epithelial homeostasis by regulating keratinocyte differentiation, p65 activity and epithelial cytokine expression, which are causally involved in the development of inflammatory skin diseases and skin tumors.