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

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

doi:10.1016/j.cellsig.2015.03.005

Cited by 19 publications

(21 citation statements)

References 41 publications

(92 reference statements)

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“…Deficiency of RIPK4 in human leads to Bartsocas-Papas syndrome, a complex congenital disorder characterized by multiple skin webs affecting the flexural surfaces accompanied by craniofacial anomalies (Kalay et al, 2012;Mitchell et al, 2012). It has been recently demonstrated that RIPK4 can phosphorylate and activate IRF6 (interferon regulatory factor 6), a transcription factor involved in skin differentiation (Kwa et al, 2014(Kwa et al, , 2015De Groote et al, 2015). Despite its critical role in development, little is known about RIPK4's molecular functions.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

Lee

Jiang

et al. 2017

The EMBO Journal

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Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post-translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin-1) by RIPK4 (receptor-interacting serine-threonine kinase 4) during epidermal differentiation. With genome-editing and mouse genetics approach, we show that loss of function of either or impairs skin differentiation and enhances epidermal carcinogenesis Phosphorylation of PKP1's N-terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK-PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

Lee

Jiang

et al. 2017

The EMBO Journal

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“…2014; Kwa et al. 2015). Our analyses also showed that 18 out of the 184 patients with NSOFCs had potentially etiologic IRF6 variants, suggesting etiologic IRF6 variants occurred in about 9% of our study cohort.…”

Section: Discussionmentioning

confidence: 99%

The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

Gowans

Busch

Mossey

et al. 2017

Molec Gen & Gen Med

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BackgroundOrofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (IRF6) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa.MethodsWe carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5′ and 3′ untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants.ResultsWe observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6, with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175‐2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants.ConclusionsThis study demonstrates that exons 4 and 7 of IRF6 are mutational ‘hotspots’ in our cohort and that IRF6 mutants‐induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high‐risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms.

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“…The transactivator function of IRF6 in oral keratinocytes can also be activated by RIPK4, for example, in response to PKC signaling (7,12). Indeed, RIPK4 was important for the stimulation of IVL, KRT13, GRHL3, and OVOL1 gene expression by the PKC agonist PMA in OKF6 cells (7).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to these markers of keratinocyte terminal differentiation, IRF6 was also shown to be important for the upregulation of other transcriptional regulators of differentiation, including GRHL3. We have previously established that IRF6 is activated by RIPK4 signaling in differentiating keratinocytes (7,12); specifically, RIPK4 stimulates the transactivator function of IRF6 by phosphorylating regulatory serine residues in its C-terminal domain (7). Significantly, the silencing of RIPK4 in OKF6 cells inhibited the stimulation of IVL, KRT13, and GRHL3 gene expression in response to P. gingivalis.…”

Section: Discussionmentioning

confidence: 99%

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Interferon Regulatory Factor 6 Promotes Keratinocyte Differentiation in Response to Porphyromonas gingivalis

Huynh

Scholz

et al. 2017

Infect Immun

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We recently demonstrated that the expression of the interferon regulatory factor 6 (IRF6) transcription factor in oral keratinocytes was stimulated by the periodontal pathogen Porphyromonas gingivalis. Here, we have established that IRF6 promotes the differentiation of oral keratinocytes in response to P. gingivalis. This was evidenced by the IRF6-dependent upregulation of specific markers of keratinocyte terminal differentiation (e.g., involucrin [IVL] and keratin 13 [KRT13]), together with additional transcriptional regulators of keratinocyte differentiation, including Grainyheadlike 3 (GRHL3) and Ovo-like zinc finger 1 (OVOL1). We have previously established that the transactivator function of IRF6 is activated by receptor-interacting protein kinase 4 (RIPK4). Consistently, the silencing of RIPK4 inhibited the stimulation of IVL, KRT13, GRHL3, and OVOL1 gene expression. IRF6 was shown to also regulate the stimulation of transglutaminase-1 (TGM1) gene expression by P. gingivalis, as well as that of small proline-rich proteins (e.g., SPRR1), which are covalently cross-linked by TGM1 to other proteins, including IVL, during cornification. The expression of the tight junction protein occludin (OCLN) was found to also be upregulated in an IRF6-dependent manner. IRF6 was demonstrated to be important for the barrier function of oral keratinocytes; specifically, silencing of IRF6 increased P. gingivalis-induced intercellular permeability and cell invasion. Taken together, our findings potentially position IRF6 as an important mediator of barrier defense against P. gingivalis. KEYWORDS differentiation, GRHL3, IRF6, keratinocyte, Porphyromonas gingivalis, RIPK4, barrier function T he oral epithelium is an important physical and immunological barrier to pathogens (1). The integrity of the epithelium is maintained through continuous cycles of keratinocyte proliferation and differentiation, whereby basal keratinocytes intermittently exit the cell cycle and undergo terminal differentiation as they migrate toward the epithelium surface, concomitantly upregulating the expression of proteins that confer mechanical strength and elasticity to the epithelium (1-3). Depending on the anatomical location, terminally differentiated keratinocytes may also become cornified through the covalent cross-linking of IVL and other cornified envelope proteins by transglutaminases (e.g., TGM1) (1, 2).IRF6 is a critical transcriptional regulator of keratinocyte differentiation (4-7). IRF6 promotes keratinocyte differentiation in part by inducing the expression of additional transcriptional regulators of differentiation, including GRHL3 and OVOL1 (5-7). GRHL3 promotes keratinocyte differentiation through its interaction with other transcription factors (e.g., LMO4) (8, 9) and by recruiting the Trithorax complex to the promoters of differentiation-associated genes (10). OVOL1 can promote keratinocyte differentiation by repressing the transcription of target genes, including c-Myc (11).The transactivator function of IRF6 can be activated...

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

Cited by 19 publications

References 41 publications

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

Interferon Regulatory Factor 6 Promotes Keratinocyte Differentiation in Response to Porphyromonas gingivalis

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