Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
Children's Hospital, Fudan University, Shanghai, China.
EMBO Rep. 2020 May 6;21(5):e48566. doi: 10.15252/embr.201948566. Epub 2020 Apr 1.
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.
皮肤表皮基底层的祖细胞在维持组织内稳态和增强皮肤伤口修复方面发挥着重要作用。表皮祖细胞的增殖、分化和细胞死亡必须得到精细调节，因为该过程的失调可导致许多皮肤疾病，包括皮肤癌。然而，皮肤内稳态所涉及的潜在分子机制仍未得到明确界定。在这项研究中，我们采用定量蛋白质组学方法，在分化的皮肤角质形成细胞中鉴定到了角蛋白分化因子 1（KDF1）和 IKKα（IκB 激酶 α）之间的一个重要相互作用。在小鼠中敲除 KDF1 或 IKKα 会导致皮肤发育出现类似但显著的异常，尤其是在表皮分化方面。通过生化和小鼠遗传学方法，我们进一步证明 IKKα 和 KDF1 的相互作用对于表皮分化是必需的。为了更深入地探究机制，我们发现 KDF1 与去泛素化酶 USP7（泛素特异性肽酶 7）相关联，并且 KDF1 可以通过去泛素化和稳定 IKKα 来调节皮肤分化。总之，我们的研究揭示了表皮分化和皮肤组织内稳态的一个重要分子机制。
