Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

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Göös , H , Fogarty , C L , Sahu , B , Plagnol , V , Rajamäki , K , Nurmi , K , Liu , X , Einarsdottir , E , Jouppila , A , Pettersson , T , Vihinen , H , Krjutskov , K , Saavalainen , P , Järvinen , A , Muurinen , M , Greco , D , Scala , G , Curtis , J , Nordström , D , Flaumenhaft , R , Vaarala , O , Kovanen , P E , Keskitalo , S , Ranki , A , Kere , J , Lehto , M , Notarangelo , L D , Nejentsev , S , Eklund , K K , Varjosalo , M , Taipale , J & Seppanen , M R J 2019 , ' Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy ' , Journal of Allergy and Clinical Immunology , vol. 144 , no. 5 , pp. 1364-1376 . https://doi.org/10.1016/j.jaci.2019.06.003

Title: Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy
Author: 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; Seppanen, Mikko R. J.
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, HUS Abdominal Center
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Institute of Biotechnology
University of Helsinki, Biosciences
University of Helsinki, Clinicum
University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, Institute of Biotechnology
University of Helsinki, Immunobiology Research Program
University of Helsinki, HUS Inflammation Center
University of Helsinki, Research Programs Unit
University of Helsinki, Institute of Biotechnology
University of Helsinki, University Management
University of Helsinki, HUS Children and Adolescents
University of Helsinki, HUSLAB
University of Helsinki, Institute of Biotechnology
University of Helsinki, HUS Inflammation Center
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUS Inflammation Center
University of Helsinki, University Management
University of Helsinki, University Management
University of Helsinki, Children's Hospital
Date: 2019-11
Language: eng
Number of pages: 13
Belongs to series: Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
URI: http://hdl.handle.net/10138/307150
Abstract: Background: CCAAT enhancer-binding protein epsilon (C/EBP epsilon) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBP epsilon 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/EBP epsilon 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/EBP epsilon. Mutated C/EBPe 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/EBP epsilon. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.
Subject: Immunologic deficiency syndromes
autoinflammatory diseases
hereditary
chemotaxis
interferons
inflammasomes
NLR family
pyrin domain-containing 3 protein
gain-of-function mutation
neomorphic mutation
BINDING-PROTEIN-EPSILON
GRANULE DEFICIENCY
ABDOMINAL-PAIN
C/EBP-EPSILON
KAPPA-B
ACTIVATION
GENE
DIFFERENTIATION
INFECTION
ATTACKS
3121 General medicine, internal medicine and other clinical medicine
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