Gain-of-function CEBPE mutation causes non-canonical autoinflammatory inflammasomopathy

Abstract Background C/EBPe is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPe is the autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. Objective The aim was to molecularly characterize the effects of C/EBPe transcription factor’s Arg219His mutation, identified in Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. Methods Genetic analysis, proteomics, genome-wide transcriptional profiling by RNA-sequencing, ChIP-sequencing and assessment of the inflammasome function of primary macrophages were performed. Results Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated non-canonical inflammasome activation due to decreased association with transcriptional repressors leading to increased chromatin occupancy and considerable changes in transcriptional activity including increased expression of NLRP3 and constitutively expressed caspase-5 in macrophages. Conclusion We describe a novel autoinflammatory disease with defective neutrophil function caused by homozygous Arg219His mutation in transcription factor C/EBPe. Mutated C/EBPe acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and non-canonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPe. Similar multiomics approaches should as well be utilized in studying other transcription factor-associated diseases.