δ-Catenin Requirement in Keratinocyte Proliferation and DNA Repair Identifies a Therapeutic Target for Photoaging

Skin photoaging is a complicated pathological process and is mainly due to UV irradiation, especially UVB irradiation. Damage induction by UVB is a complex process, involving intricate molecular mechanisms. The formation of bulky photoproducts in the DNA globally affects transcription and splicing and results in the dysfunction of keratinocytes. In this study, we show that δ-catenin is predominantly distributed in keratinocytes of the skin epidermis and functionally accelerates cell proliferation and DNA repair. Ex vivo protein profiling reveals that δ-catenin upregulates the phosphorylation of RSK2^Ser-227 by enhancing the interaction between PDK1 and RSK2 and thereby induces the nuclear accumulation of YB1 to promote proliferation and DNA repair. Moreover, δ-catenin overexpression induces in vivo keratinocyte proliferation and DNA repair in UVB-irradiated mouse skin. Notably, acidic fibroblast GF/FGFR1 is identified as one of the key upstream signalings of δ-catenin by inducing δ-catenin stabilization. The involvement of δ-catenin in keratinocyte proliferation and DNA repair may suggest δ-catenin as a target for the treatment of UVB damage.