IKKα controls formation of the epidermis independently of NF-κB

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Abstract
The IKKα and IKKβ catalytic subunits of IκB kinase (IKK) share 51% amino-acid identity and similar biochemical activities: they both phosphorylate IκB proteins at serines that trigger their degradation1,2,3,4. IKKα and IKKβ differ, however, in their physiological functions. IKKβ and the IKKγ/NEMO regulatory subunit are required for activating NF-κB by pro-inflammatory stimuli and preventing apoptosis induced by tumour necrosis factor-α (refs 5,6,7,8,9,10,11). IKKα is dispensable for these functions, but is essential for developing the epidermis and its derivatives12,13,14,15. The mammalian epidermis is composed of the basal, spinous, granular and cornified layers16. 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-κB, as in Ikkα-/- mice12,13,14,15, results in epidermal thickening but does not block terminal differentiation17,18. It has been proposed19,20 that the epidermal defect in Ikkα-/- mice may be due to the failed activation of NF-κB. Here we show that the unique function of IKKα in control of keratinocyte differentiation is not exerted through its IκB kinase activity or through NF-κB. Instead, IKKα controls production of a soluble factor that induces keratinocyte differentiation.