Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

• Published in: Journal of allergy and clinical immunology Vol. 144; no. 5; pp. 1364 - 1376
• Main Authors: Göös, Helka, Fogarty, Christopher L., Sahu, Biswajyoti, Plagnol, Vincent, Rajamäki, Kristiina, Nurmi, Katariina, Liu, Xiaonan, Einarsdottir, Elisabet, Jouppila, Annukka, Pettersson, Tom, Vihinen, Helena, Krjutskov, Kaarel, Saavalainen, Päivi, Järvinen, Asko, Muurinen, Mari, Greco, Dario, Scala, Giovanni, Curtis, James, Nordström, Dan, Flaumenhaft, Robert, Vaarala, Outi, Kovanen, Panu E., Keskitalo, Salla, Ranki, Annamari, Kere, Juha, Lehto, Markku, Notarangelo, Luigi D., Nejentsev, Sergey, Eklund, Kari K., Varjosalo, Markku, Taipale, Jussi, Seppänen, Mikko R.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2019; Elsevier Limited
• Subjects: Abdomen; Age; Aged; autoinflammatory diseases; Bacterial infections; Caspase-5; Caspases - genetics; Caspases - metabolism; CCAAT-Enhancer-Binding Proteins - genetics; Cells, Cultured; chemotaxis; Chromatin; Deoxyribonucleic acid; DNA; Female; Fever; Flow cytometry; Gain of Function Mutation - genetics; gain-of-function mutation; Gene Expression Profiling; Genetic analysis; Genomes; Granulocytes; hereditary; Hospitals; Human subjects; Humans; Immune system; Immunodeficiency; Immunologic deficiency syndromes; Immunologic Deficiency Syndromes - genetics; Immunoprecipitation; Infections; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Inflammation - genetics; interferons; Lymphatic system; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Microscopy; Mutation; neomorphic mutation; Neutrophils; Neutrophils - physiology; NLR family; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pain; Pedigree; Proteins; Proteomics; pyrin domain-containing 3 protein; Pyrin protein; Repressors; Ribonucleic acid; RNA; Sequence Analysis, RNA; Transcription factors; Ulcers; Up-Regulation; Finland; NLR family; C/EBP; autoinflammatory diseases; PPI; Immunologic deficiency syndromes; ChIP; NF-κB; interferons; pyrin domain-containing 3 protein; RNA-seq; FDR; NLRP3; AID; CAIN; WT; chemotaxis; GOF; LOF; gain-of-function mutation; inflammasomes; PID; SGD; SMRC2; STAT; JAK; ChIP-seq; neomorphic mutation; hereditary; FC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2019.06.003

CCAAT enhancer–binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor–associated diseases. [Display omitted]