Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions

Abstract

IRF6 and RIPK4 are critical regulators of keratinocyte differentiation and their mutation cause the developmental syndromes Van der Woude syndrome (VWS) and Bartsocas-Papas syndrome (BPS), respectively. RIPK4 promotes keratinocyte differentiation, in part, by inducing IRF6 transactivator function through the phosphorylation of its C-terminal domain at Ser413 and Ser424. Although more than. 200 IRF6 mutations have been identified in VWS, a p.Arg412X nonsense mutation is particularly prevalent. A RIPK4 p.Ser376X nonsense mutation in BPS was also recently identified. Here, we demonstrated for the first time that the truncation of IRF6 at Arg412 causes its rapid proteasome-dependent degradation...