TY - JOUR
T1 - Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy
AU - Göös, H.
AU - Fogarty, Christopher L.
AU - Sahu, Biswajyoti
AU - Plagnol, Vincent
AU - Rajamäki, Kristiina
AU - Nurmi, Katariina
AU - Liu, Xiaonan
AU - Einarsdottir, Elisabet
AU - Jouppila, Annukka
AU - Pettersson, Tom
AU - Vihinen, Helena
AU - Krjutskov, Kaarel
AU - Saavalainen, P. ivi
AU - Järvinen, Asko
AU - Muurinen, Mari
AU - Greco, D.
AU - Scala, Giovanni
AU - Curtis, J.
AU - Nordström, Dan
AU - Flaumenhaft, Robert
AU - Vaarala, Outi
AU - Kovanen, Panu E.
AU - Keskitalo, S.
AU - Ranki, Annamari
AU - Kere, Juha
AU - Lehto, Markku
AU - Notarangelo, Luigi D.
AU - Nejentsev, Sergey
AU - Eklund, Kari K.
AU - Varjosalo, Markku
AU - Taipale, J.
AU - Seppänen, Mikko R. J.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - Immunologic deficiency syndromes
KW - NLR family
KW - autoinflammatory diseases
KW - chemotaxis
KW - gain-of-function mutation
KW - hereditary
KW - inflammasomes
KW - interferons
KW - neomorphic mutation
KW - pyrin domain-containing 3 protein
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85070239795&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31201888
U2 - https://doi.org/10.1016/j.jaci.2019.06.003
DO - https://doi.org/10.1016/j.jaci.2019.06.003
M3 - Article
C2 - 31201888
SN - 0091-6749
VL - 144
SP - 1364
EP - 1376
JO - Journal of allergy and clinical immunology
JF - Journal of allergy and clinical immunology
IS - 5
ER -