title: 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. 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.
authors.affiliation: 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.
authors.forename: Mei Qi
authors.initials: MQ
authors.lastname: Kwa
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huynh
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, The University of Melbourne, Victoria 3010, Australia; Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Reynolds
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria 3010, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
authors.affiliation: 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.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Scholz
mesh_terms: D000015:Abnormalities, Multiple / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002971:Cleft Lip / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000378:metabolism / Q000473:pathology; D003560:Cysts / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D005124:Eye Abnormalities / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007717:Knee / Q000002:abnormalities / Q000473:pathology; D008046:Lip / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction; D013576:Syndactyly / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D051176:beta Catenin; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cleft lip/palate; IRF6; Mutation; Protein degradation; RIPK4