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

Wim Declercq (1) , Saskia Lippens (1) , Sylvie Lefebvre (1) , Barbara Gilbert (1) , Mozes Sze (1) , Michael Devos (1) , Lars Vereecke (1) , Conor Mcguire (1) , Christopher J. Guerin (1) , Peter Vandenabeele (1) , Manolis Pasparakis (1) , Marja L Mikkola (1) , Rudi Beyaert (1) , Geert van Loo (1) , Kelly Verhelst (1)

1 Department for Molecular Biomedical Research

The ubiquitin-editing enzyme A20 (TNFAIP3) serves as a critical brake on NF-κB signaling. In humans, polymorphisms in or near the A20 gene are associated with several inflammatory disorders, including psoriasis. We show here that epidermis-specific A20 knockout mice (A20EKO) develop keratinocyte hyperproliferation, but no signs of skin inflammation, such as immune cell infiltration. However, A20EKO mice clearly developed ectodermal organ abnormalities, including disheveled hair, longer nails and sebocyte hyperplasia. This phenotype resembles that of mice overexpressing EDA-A1 or its receptor EDAR, suggesting that A20 negatively controls EDAR signaling. We found that A20 inhibited EDAR-induced NF-κB signaling independent from its de-ubiquitinating activity. In addition, A20 expression was induced by EDA-A1 in embryonic skin explants, where its expression was confined to the hair placodes, known to be the site of EDAR expression. In summary, our data indicate that EDAR-induced NF-κB levels are controlled by A20, which acts as a negative feedback regulator, to assure proper skin homeostasis and epidermal appendage development.

Mots clés: skin; A20; knockout; NF-kappaB; EDA

Wim Declercq, Saskia Lippens, Sylvie Lefebvre, Barbara Gilbert, Mozes Sze, et al.. Keratinocyte-specific ablation of the NF-κB regulatory protein A20 (TNFAIP3) reveals a role in the control of epidermal homeostasis. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.55⟩. ⟨hal-00640518⟩