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 & Seppänen , 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 .

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; Seppänen, Mikko R. J.
Contributor organization: Institute of Biotechnology
Helsinki Institute of Life Science HiLIFE, Joint Activities
HUS Abdominal Center
Nefrologian yksikkö
University of Helsinki
Diabetes and Obesity Research Program
Research Programs Unit
Genome-Scale Biology (GSB) Research Program
Faculty of Medicine
Research Programme of Molecular Medicine
Päivi Marjaana Saavalainen / Principal Investigator
HUS Helsinki and Uusimaa Hospital District
HUS Internal Medicine and Rehabilitation
University Management
Department of Medicine
Electron Microscopy
Immunobiology Research Program
Department of Medical and Clinical Genetics
HUS Inflammation Center
Infektiosairauksien yksikkö
STEMM - Stem Cells and Metabolism Research Program
Reumatologian yksikkö
HUS Children and Adolescents
Children's Hospital
Department of Pathology
Department of Dermatology, Allergology and Venereology
Juha Kere / Principal Investigator
Molecular Systems Biology
Jussi Taipale / Principal Investigator
Date: 2019-11
Language: eng
Number of pages: 13
Belongs to series: Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
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
NLR family
pyrin domain-containing 3 protein
gain-of-function mutation
neomorphic mutation
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion

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