A novel regulatory relationship between RIPK4 and ELF3 in keratinocytes.
Keratinocytes are central to the barrier functions of surface epithelia, such as the gingiva and epidermis. RIPK4 is a key regulator of keratinocyte differentiation; however, the signalling pathways in which it functions remain poorly defined. In this study, we identified a regulatory relationship between RIPK4 and ELF3, an ETS family transcription factor. RIPK4 was shown to be important for the upregulation of ELF3 gene expression by the PKC agonist PMA in both oral and epidermal keratinocytes. RIPK4 promotes keratinocyte differentiation in part by phosphorylating and thereby activating the IRF6 transcription factor. Significantly, silencing of IRF6 inhibited the PMA-inducible expression of ELF3. A role for the GRHL3 transcription factor, a downstream target gene of IRF6, in the regulation of ELF3 expression was similarly demonstrated. ELF3 has previously been shown to regulate the expression of SPPR1A and SPRR1B, small proline-rich proteins that contribute to the cornification of keratinocytes. Consistently, RIPK4 and IRF6 were important for the PMA-inducible expression of SPRR1A and SPRR1B. They were also important for the upregulation of TGM1, a transglutaminase that catalyses the cross-linking of proteins, including small proline-rich proteins, during keratinocyte cornification. RIPK4 was also shown to upregulate the expression of TGM2 independently of IRF6. Collectively, our findings position RIPK4 upstream of a hierarchal IRF6-GRHL3-ELF3 transcription factor pathway in keratinocytes, as well as provide insight into a potential role for RIPK4 in the regulation of keratinocyte cornification.
Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia.
Glen M
GM
Scholz
Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia.
Nur S
NS
Sulaiman
Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia.
Sahar
S
Al Baiiaty
Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia.
Mei Qi
MQ
Kwa
Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia. Electronic address: e.reynolds@unimelb.edu.au.
Eric C
EC
Reynolds
D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008954:Models, Biological; D014176:Protein Biosynthesis / Q000187:drug effects; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism
D055233:Cornified Envelope Proline-Rich Proteins; D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; C473143:GRHL3 protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D011500:Protein Synthesis Inhibitors; D050783:Proto-Oncogene Proteins c-ets; C000717608:TGM2 protein, human; D014157:Transcription Factors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C105804:transglutaminase 1; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases; D019204:GTP-Binding Proteins
Barrier function; Cornification; Differentiation; ELF3; IRF6; RIPK4