Keratinocyte-specific ablation of the NF-κB regulatory protein A20 (TNFAIP3) reveals a role in the control of epidermal homeostasis

The study demonstrated that the ubiquitin-editing enzyme A20 (TNFAIP3) played a crucial role in regulating NF-κB signaling in the epidermis. Epidermis-specific A20-knockout mice exhibited keratinocyte hyperproliferation and ectodermal organ abnormalities, such as disheveled hair, longer nails, and sebocyte hyperplasia, but did not show signs of skin inflammation. These findings suggested that A20 negatively controlled EDAR signaling, independent of its de-ubiquitinating activity, and was induced by EDA-A1 in embryonic skin, particularly in hair placodes. The data indicated that A20 acted as a negative feedback regulator of EDAR-induced NF-κB levels, ensuring proper skin homeostasis and development of epidermal appendages.