RIPK4 regulates keratinocyte differentiation via an IKKα-IRF6 signaling axis

RIPK4, IKKα and IRF6 are important regulators of epidermal development and homeostasis. The phenotypes of mice or men carrying inactivating variants show similar and overlapping defects in epidermal development, however, whether they act in a linear or parallel signaling pathway remains poorly understood. We show that in cultured normal human primary keratinocytes RIPK4 as well as IKKα and IRF6 control the expression of a genetic program responsible for formation of the cornified envelope, tight junctions and the lipid barrier. Both IKKα and RIPK4 can lead to IRF6 phosphorylation and activate IRF6 reporter activity in a kinase-dependent manner and RIPK4-induced IRF6 reporter activation is impaired in an IKKα-deficient background. We found that the RIPK4 kinase domain and its kinase activity are important for the interaction with IKKα and IRF6. In keratinocytes, IKKα and IRF6 regulate RIPK4-induced cytoskeletal rearrangements and expression of tight junction proteins such as Occludin and Claudin-4. Taken together, our data indicate that RIPK4 can engage IKKα to activate the IRF6 transcription factor to switch on keratinocyte differentiation.