Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy - 05/11/19

Doi : 10.1016/j.jaci.2019.06.003

Helka Göös, MSc ^a,^{∗
These authors contributed equally to this work.}, Christopher L. Fogarty, PhD ^b,^c,^d,^e,^{∗
These authors contributed equally to this work.}, Biswajyoti Sahu, PhD ^f,^{∗
These authors contributed equally to this work.}, Vincent Plagnol, PhD ^g, Kristiina Rajamäki, PhD ^h, Katariina Nurmi, PhD ^h, Xiaonan Liu, MSc ^a, Elisabet Einarsdottir, PhD ^i,^j,^k, Annukka Jouppila, MSc ^l, Tom Pettersson, MD, PhD ^h,^m, Helena Vihinen, DSc ⁿ, Kaarel Krjutskov, PhD ^j,^l,^o, Päivi Saavalainen, PhD ^p,^q, Asko Järvinen, MD, PhD ^r, Mari Muurinen, MD ^i,^k, Dario Greco, PhD ^a,^s, Giovanni Scala, PhD ^a,^s, James Curtis, PhD ^t, Dan Nordström, MD, PhD ^h,^u, Robert Flaumenhaft, MD, PhD ^v, Outi Vaarala, MD, PhD ^w,^x, Panu E. Kovanen, MD, PhD ^y, Salla Keskitalo, PhD ^a, Annamari Ranki, MD, PhD ^z, Juha Kere, MD, PhD ^i,^j,^k,^aa, Markku Lehto, PhD ^b,^c,^d, Luigi D. Notarangelo, MD ^bb, Sergey Nejentsev, MD, PhD ^t, Kari K. Eklund, MD, PhD ^h,^u,^cc,^{‡
These authors contributed equally to this work.}, Markku Varjosalo, PhD ^a,^{‡
These authors contributed equally to this work.}, Jussi Taipale, PhD ^f,^dd,^ee,^{‡
These authors contributed equally to this work.}, Mikko R.J. Seppänen, MD, PhD ^r,^ff,^⁎,^{‡
These authors contributed equally to this work.}
^a Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
^b Folkhälsan Research Center, Helsinki, Finland
^c Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^d Diabetes & Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland
^e Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
^f Research Programs Unit, Genome-Scale Biology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
^g University College London Genetics Institute, University College London, London, United Kingdom
^h Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
ⁱ Folkhälsan Institute of Genetics, Helsinki, Finland
^j Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
^k Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland
^l Helsinki University Hospital Research Institute, Helsinki, Finland
^m Department of Internal Medicine and Rehabilitation, Helsinki University Hospital, Helsinki, Finland
ⁿ Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
^o Competence Centre on Health Technologies, Tartu, Estonia
^p Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
^q Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
^r Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^s Faculty of Medicine and Life Sciences & Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland
^t Department of Medicine, University of Cambridge, Cambridge, United Kingdom
^u Department of Rheumatology, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^v Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Mass
^w Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^x Respiratory, Inflammation and Autoimmunity, Innovative Medicine, AstraZeneca, Mölndal, Sweden
^y Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, Helsinki, Finland
^z Department of Dermatology, Allergology and Venereal Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^aa School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, United Kingdom
^bb Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^cc Orton Orthopaedic Hospital and Research Institute, Invalid Foundation, Helsinki, Finland
^dd Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
^ee Department of Biochemistry, Cambridge University, Cambridge, United Kingdom
^ff Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

^∗Corresponding author: Mikko R. J. Seppänen, MD, PhD, Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 281, FI-00029 HUS Helsinki, Finland.Rare Diseases Center and Pediatric Research CenterChildren's HospitalUniversity of Helsinki and Helsinki University HospitalPO Box 281HelsinkiFI-00029 HUSFinland

Abstract

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.

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Graphical abstract

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

Abbreviations used : AID, CAIN, C/EBP, ChIP, ChIP-seq, FC, FDR, GOF, JAK, LOF, NF-κB, NLRP3, PID, PPI, RNA-seq, SGD, SMRC2, STAT, WT

Plan

Methods

Functional studies of CEBPE mutation

Functional studies of patients' primary cells

Results

Case reports

Genetic analysis found a novel homozygous CEBPE mutation

Widely altered C/EBPε PPIs

Increased chromatin occupancy of Arg219His C/EBPε

Pronounced transcriptional changes in mutated unstimulated granulocytes

Comparison of results for differentially expressed genes with those of other studies

Transcriptional changes after LPS and bacterial DNA stimulation

Transcriptional changes after interferon stimulation

mRNA levels in PBMCs

NLRP3 inflammasome activation in monocytes and macrophages by a noncanonical inflammasome

Neutrophils displayed impaired CD66b expression

Normal neutrophil and platelet morphology

Posttranscriptional compensatory mechanisms

Discussion

This study was supported by the Orion Research Foundation (to H.G.); the Paulo Foundation ja Maire Lisko Foundation (to K.R.); Helsinki University Hospital Research funds (to A.R. and M.R.J.S.), an Academy of Finland Post-doctoral Fellowship (274555, to B.S.); the Päivikki and Sakari Sohlberg Foundation and the Yrjö Jahnsson Foundation (to K.N.); the Division of Intramural Research, National Institute of Health, National Institutes of Health, Bethesda, Maryland (to L.D.N.); the Folkhälsan Research Foundation and the Novo Nordisk (to M.L.); the Academy of Finland (288475 and 294173, to M.V.); the Sigrid Jusélius Foundation (to M.V.); the Finnish Foundation for Pediatric Research (to M.R.J.S.); a University of Helsinki Three-year Research Grant, Biocentrum Helsinki, Biocentrum Finland, and HiLIFE (to M.V.); the Instrumentarium Research Foundation (to M.V. and K.K.E.); and Finska Läkaresällskapet (to K.K.E. and D.N.).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 144 - N° 5

P. 1364-1376 - novembre 2019 Retour au numéro

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Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy - 05/11/19

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Plan

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