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

Mei Qi Kwa; Jennifer Huynh; Eric C Reynolds; John A Hamilton; Glen M Scholz

doi:10.1016/j.cellsig.2015.03.005

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

Cell Signal. 2015 Jul;27(7):1509-16. doi: 10.1016/j.cellsig.2015.03.005. Epub 2015 Mar 14.

Authors

Mei Qi Kwa¹, Jennifer Huynh¹, Eric C Reynolds², John A Hamilton³, Glen M Scholz⁴

Affiliations

¹ Oral Health Cooperative Research Centre, Melbourne Dental School, The University of Melbourne, Victoria 3010, Australia; Bio21 Institute, The University of Melbourne, Victoria 3010, Australia; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria 3010, Australia.
² Oral Health Cooperative Research Centre, Melbourne Dental School, The University of Melbourne, Victoria 3010, Australia; Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.
³ Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria 3010, Australia.
⁴ Oral Health Cooperative Research Centre, Melbourne Dental School, The University of Melbourne, Victoria 3010, Australia; Bio21 Institute, The University of Melbourne, Victoria 3010, Australia; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria 3010, Australia. Electronic address: glenms@unimelb.edu.au.

PMID: 25784454
DOI: 10.1016/j.cellsig.2015.03.005

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.

Keywords: Cleft lip/palate; IRF6; Mutation; Protein degradation; RIPK4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / metabolism
Abnormalities, Multiple / pathology
Cell Line
Cleft Lip / metabolism
Cleft Lip / pathology
Cleft Palate / metabolism
Cleft Palate / pathology
Cysts / metabolism
Cysts / pathology
Cytoplasm / metabolism
Eye Abnormalities / metabolism
Eye Abnormalities / pathology
HEK293 Cells
Half-Life
Humans
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
Knee / abnormalities
Knee / pathology
Lip / abnormalities
Lip / metabolism
Lip / pathology
Mutation, Missense
NF-kappa B / metabolism
Phosphorylation
Promoter Regions, Genetic
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein Structure, Tertiary
Recombinant Fusion Proteins / biosynthesis
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Signal Transduction
Syndactyly / metabolism
Syndactyly / pathology
Transcriptional Activation
beta Catenin / metabolism

Substances

IRF6 protein, human
Interferon Regulatory Factors
NF-kappa B
Recombinant Fusion Proteins
beta Catenin
RIPK4 protein, human
Protein Serine-Threonine Kinases
JNK Mitogen-Activated Protein Kinases

Supplementary concepts

Popliteal Pterygium Syndrome, Lethal Type
Van der Woude syndrome