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.

NF-κB家族的转录因子通过激活与病原体清除有关的趋化因子，细胞因子和抗菌肽的表达，在免疫应答中起着至关重要的作用。IκBζ是一种非典型的核IκB蛋白，是特定NF-κB靶基因的选择性共激活因子，最近已被确定为皮肤免疫的重要调节剂。这项研究发现，IκBζ在感知真菌葡聚糖zymosan A的角质形成细胞中强烈诱导。此外，IκBζ对于促炎基因（如IL6，CXCL5，IL1B或S100A9）的最佳表达至关重要。此外，这项研究发现IκBζ不仅受转录水平的调控，而且受磷酸化事件的调控。这项研究确定了几个IκBζ磷酸化位点，包括位于蛋白质N端的苏氨酸残基的保守簇，可以被MAPK磷酸化。出乎意料的是，在该苏氨酸簇上的IκBζ磷酸化促进了组蛋白脱乙酰基酶1募集到特定靶基因启动子，并因此负面地控制了转录。综上所述，这项研究提出了一种抗真菌应答如何转化为促炎细胞因子表达的模型，并强调了角质形成细胞中NF-κB应答调节的另一层复杂性。