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

Cellular Signalling
Mei Qi KwaGlen M Scholz

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. The truncation of IRF6 also prevented the induction of its transactivator function by RIPK4. Similarly, the p.Ser376X mutation in RIPK4 impaired its induction of IRF6 transactivator function. The mutation also inhibited the stabilisation of β-catenin by RIPK4, and thus may additionally impair Wnt signalling. Collectively, our findings provide important mechanistic insight into how the p.Arg412X and p.Ser376X mutations may cause VWS and BPS, respectively.

References

Feb 12, 2009·Nature Reviews. Molecular Cell Biology·Cédric Blanpain, Elaine Fuchs
Sep 27, 2014·Cell Death and Differentiation·G FilomeniF Cecconi

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Citations

Sep 4, 2015·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Youssef A Kousa, Brian C Schutte
Jun 19, 2015·Human Molecular Genetics·Stephen R F Twigg, Andrew O M Wilkie
Sep 27, 2016·Cellular Signalling·Glen M ScholzEric C Reynolds
Apr 1, 2017·Molecular Genetics & Genomic Medicine·Lord Jephthah Joojo GowansAzeez Butali
May 1, 2018·Structure·Christine S HuangSarah G Hymowitz

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