IKKα controls formation of the epidermis independently of NF-κB

The IKK alpha and IKK beta catalytic subunits of I kappaB kinase (IKK) share 51% amino-acid identity and similar biochemical activities: they both phosphorylate I kappaB proteins at serines that trigger their degradation(1-4). IKK alpha and IKK beta differ, however, in their physiological functions. IKK beta and the IKK gamma /NEMO regulatory subunit are required for activating NF-kappaB by pro-inflammatory stimuli and preventing apoptosis induced by tumour necrosis factor-alpha (refs 5-11). IKK alpha is dispensable for these functions, but is essential for developing the epidermis and its derivatives(12-15). The mammalian epidermis is composed of the basal, spinous, granular and cornified layers(16). Only basal keratinocytes can proliferate and give rise to differentiated derivatives, which on full maturation undergo enucleation to generate the cornified layer. Curiously, keratinocyte-specific inhibition of NF-kappaB, as in Ikk alpha (-/-) mice(12-15), results in epidermal thickening but does not block terminal differentiation(17,18). It has been proposed(19,20) that the epidermal defect in Ikk alpha (-/-) mice may be due to the failed activation of NF-kappaB. Here we show that the unique function of IKK alpha in control of keratinocyte differentiation is not exerted through its I kappaB kinase activity or through NF-kappaB. Instead, IKK alpha controls production of a soluble factor that induces keratinocyte differentiation.