IKKa signaling in the nucleus or cytoplasm of keratinocytes leads to opposite skin phenotypes.
The skin exerts essential roles for the organism survival, such as environmental barrier and immune functions. IKKa is known as an essential protein for skin homeostasis. However, the functions performed by IKKa in the skin and the mechanisms it employs are largely unknown, leading to contradictory interpretations and results regarding the consequences of its deregulation in pathologies such as non-melanoma skin cancer (NMSC). Here, using our previously generated transgenic mouse models which express IKKa in the cytoplasm (C-IKKa mice) or in the nucleus (N-IKKa mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKa distinctly regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, as well as the inflammatory response of the skin. As a result, N-IKKa mice show an atrophic epidermis with exacerbated terminal differentiation, reminiscent of alterations observed in patients with ichthyosis. Conversely, C-IKKa mice display a hyperplastic epidermis with impaired epidermal differentiation and pustular inflammation, resembling patients with pustular psoriasis. Interestingly, C-IKKa keratinocytes are almost devoid of nuclear IKKa due to endogenous IKKa downregulation. However, these changes in the skin of C-IKKa mice do not lead to the development of squamous cell carcinomas (SCCs), unlike N-IKKa mice, which develop spontaneous SCCs. Overall design: Comparative gene expression profiling analysis of RNA-seq data for skin from wild type or transgenic mice expressing exogenoues IKKalpha  in the nucleus (N-IKKa mice) and in the cytoplasm (C-IKKa mice) of keratinocytes.