Receptor-Interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation [Signal Transduction]

September 22nd, 2014 by Kwa, M. Q., Huynh, J., Aw, J., Zhang, L., Nguyen, T., Reynolds, E. C., Sweet, M. J., Hamilton, J. A., Scholz, G. M.

Receptor-Interacting Protein Kinase 4 (RIPK4) and Interferon Regulatory Factor 6 (IRF6) are critical regulators of keratinocyte differentiation and their mutation cause the related developmental epidermal disorders Bartsocas-Papas Syndrome and Popliteal Pterygium Syndrome, respectively. However, the signaling pathways in which RIPK4 and IRF6 operate to regulate keratinocyte differentiation are poorly defined. Here, we identify and mechanistically define a direct functional relationship between RIPK4 and IRF6. Gene promoter reporter and in vitro kinase assays, co-immunoprecipitation experiments, and confocal microscopy demonstrated that RIPK4 directly regulates IRF6 trans-activator activity and nuclear translocation. Gene knock-down and overexpression studies indicated that the RIPK4-IRF6 signaling axis controls the expression of key transcriptional regulators of keratinocyte differentiation, including Grainyhead-Like 3 and OVO-Like 1. Additionally, we demonstrate that the p.Ile121Asn missense mutation in RIPK4, which was recently identified in Bartsocas-Papas Syndrome, inhibits its kinase activity, thereby preventing RIPK4-mediated IRF6 activation and nuclear translocation. We show through mutagenesis-based experiments that Ser-413 and Ser-424 in IRF6 are important for its activation by RIPK4. RIPK4 is also important for the regulation of IRF6 expression by the protein kinase C pathway. Our findings therefore not only provide important mechanistic insights into the regulation of keratinocyte differentiation by RIPK4 and IRF6, but they also suggest one mechanism by which mutations in RIPK4 may cause epidermal disorders (e.g. Bartsocas-Papas Syndrome), namely by the impaired activation of IRF6 by RIPK4.
  • Posted in Journal of Biological Chemistry, Publications
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