Threonine Phosphorylation of IκBζ Mediates Inhibition of Selective Proinflammatory Target Genes

J Invest Dermatol. 2020 Sep;140(9):1805-1814.e6. doi: 10.1016/j.jid.2019.12.036. Epub 2020 Feb 6.


Transcription factors of the NF-κB family play a crucial role for immune responses by activating the expression of chemokines, cytokines, and antimicrobial peptides involved in pathogen clearance. IκBζ, an atypical nuclear IκB protein and selective coactivator of particular NF-κB target genes, has recently been identified as an essential regulator for skin immunity. This study discovered that IκBζ is strongly induced in keratinocytes that sense the fungal glucan zymosan A. Additionally, IκBζ is essential for the optimal expression of proinflammatory genes, such as IL6, CXCL5, IL1B, or S100A9. Moreover, this study found that IκBζ was not solely regulated on the transcriptional level but also by phosphorylation events. This study identified several IκBζ phosphorylation sites, including a conserved cluster of threonine residues located in the N-terminus of the protein, which can be phosphorylated by MAPKs. Surprisingly, IκBζ phosphorylation at this threonine cluster promoted the recruitment of histone deacetylase 1 to specific target gene promoters and, thus, negatively controlled transcription. Taken together, this study proposes a model of how an antifungal response translates to the expression of proinflammatory cytokines and highlights an additional layer of complexity in the regulation of the NF-κB responses in keratinocytes.