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Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy
Helka Göös1, Christopher L Fogarty2, Biswajyoti Sahu3
1Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
The Journal of Allergy and Clinical Immunology
|June 16, 2019
Summary
A novel mutation in CCAAT enhancer-binding protein epsilon (C/EBPε) causes a new autoinflammatory disease with impaired neutrophil function. This C/EBPε mutation leads to widespread gene dysregulation and altered inflammasome activation.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor crucial for myeloid cell differentiation.
- Previously, C/EBPε mutations were only linked to neutrophil-specific granule deficiency, causing severe immune impairment.
Observation:
- A Finnish family presented with a previously uncharacterized autoinflammatory and immunodeficiency syndrome.
- A specific Arg219His mutation in the C/EBPε gene was identified in affected individuals.
Findings:
- The Arg219His mutation resulted in a novel genome-wide gain-of-function mechanism for C/EBPε.
- This led to dysregulated transcription of 464 genes, including increased NLRP3 and caspase-5 expression in macrophages.
- Defective noncanonical inflammasome activation was observed due to altered interactions with transcriptional repressors.
Implications:
- This study describes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency.
- The findings reveal C/EBPε as a regulator of both the inflammasome and interferome.
- The multiomics approach highlights a potential mechanism for other transcription factor-associated diseases.
Keywords:
Immunologic deficiency syndromesNLR familyautoinflammatory diseaseschemotaxisgain-of-function mutationhereditaryinflammasomesinterferonsneomorphic mutationpyrin domain-containing 3 proteinMore Related Videos
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