Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

H. Göös, Christopher L. Fogarty, Biswajyoti Sahu, Vincent Plagnol, Kristiina Rajamäki, Katariina Nurmi, Xiaonan Liu, Elisabet Einarsdottir, Annukka Jouppila, Tom Pettersson, Helena Vihinen, Kaarel Krjutskov, P. ivi Saavalainen, Asko Järvinen, Mari Muurinen, D. Greco, Giovanni Scala, J. Curtis, Dan Nordström, Robert FlaumenhaftOuti Vaarala, Panu E. Kovanen, S. Keskitalo, Annamari Ranki, Juha Kere, Markku Lehto, Luigi D. Notarangelo, Sergey Nejentsev, Kari K. Eklund, Markku Varjosalo, J. Taipale, Mikko R. J. Seppänen

Research output: Contribution to journalArticleAcademicpeer-review

33 Citations (Scopus)


Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.
Original languageEnglish
Pages (from-to)1364-1376
Number of pages13
JournalJournal of allergy and clinical immunology
Issue number5
Publication statusPublished - 1 Nov 2019
Externally publishedYes


  • Immunologic deficiency syndromes
  • NLR family
  • autoinflammatory diseases
  • chemotaxis
  • gain-of-function mutation
  • hereditary
  • inflammasomes
  • interferons
  • neomorphic mutation
  • pyrin domain-containing 3 protein

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