Regulation of epidermal differentiation through KDF1‐mediated deubiquitination of IKKα

Progenitor cells at the basal layer of skin epidermis play an essential role in maintaining tissue homeostasis and enhancing wound repair in skin. The proliferation, differentiation, and cell death of epidermal progenitor cells have to be delicately regulated, as deregulation of this process can lead to many skin diseases, including skin cancers. However, the underlying molecular mechanisms involved in skin homeostasis remain poorly defined. In this study, with quantitative proteomics approach, we identified an important interaction between KDF1 (keratinocyte differentiation factor 1) and IKKα (IκB kinase α) in differentiating skin keratinocytes. Ablation of either KDF1 or IKKα in mice leads to similar but striking abnormalities in skin development, particularly in skin epidermal differentiation. With biochemical and mouse genetics approach, we further demonstrate that the interaction of IKKα and KDF1 is essential for epidermal differentiation. To probe deeper into the mechanisms, we find that KDF1 associates with a deubiquitinating protease USP7 (ubiquitin‐specific peptidase 7), and KDF1 can regulate skin differentiation through deubiquitination and stabilization of IKKα. Taken together, our study unravels an important molecular mechanism underlying epidermal differentiation and skin tissue homeostasis. Synopsis KDF1 (Keratinocyte Differentiation Factor 1) promotes the deubiquitination and stability of IKKα by recruiting USP7 (Ubiquitin Specific Peptidase 7). This interaction is essential for skin epidermal differentiation. IKKα interaction with KDF1 is essential for epidermal differentiation. KDF1associates with USP7, which mediates IKKα deubiquitination and stabilization. Graphical Abstract KDF1 (Keratinocyte Differentiation Factor 1) promotes the deubiquitination and stability of IKKα by recruiting USP7 (Ubiquitin Specific Peptidase 7). This interaction is essential for skin epidermal differentiation.