Threonine phosphorylation of IκBζ mediates inhibition of selective proinflammatory target genes.

Grondona P, Bucher P, Schmitt A, Schönfeld C, Streibl B, Müller A, Essmann F, Liberatori S, Mohammed S, Hennig A, Kramer D, Schulze-Osthoff K, Hailfinger S

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. In the present study, we discovered that IκBζ is strongly induced in keratinocytes sensing the fungal glucan zymosan A and that IκBζ is essential for the optimal expression of proinflammatory genes, such as IL6, CXCL5, IL1B or S100A9. Moreover, we found that IκBζ was not solely regulated on the transcriptional level but also by phosphorylation events. We 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 HDAC1 to specific target gene promoters and thus and thus negatively controlled transcription. Taken together, we propose a model of how an anti-fungal response translates to the expression of proinflammatory cytokines and highlight an additional layer of complexity in the regulation of the NF-κB responses in keratinocytes.


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February, 2020


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