Frontiers in Immunology (Oct 2018)
A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
- Marieke De Bruyne,
- Marieke De Bruyne,
- Marieke De Bruyne,
- Levi Hoste,
- Levi Hoste,
- Delfien J. Bogaert,
- Delfien J. Bogaert,
- Delfien J. Bogaert,
- Delfien J. Bogaert,
- Lien Van den Bossche,
- Lien Van den Bossche,
- Simon J. Tavernier,
- Simon J. Tavernier,
- Eef Parthoens,
- Eef Parthoens,
- Mélanie Migaud,
- Deborah Konopnicki,
- Jean Cyr Yombi,
- Bart N. Lambrecht,
- Bart N. Lambrecht,
- Sabine van Daele,
- Ana Karina Alves de Medeiros,
- Lieve Brochez,
- Rudi Beyaert,
- Elfride De Baere,
- Anne Puel,
- Jean-Laurent Casanova,
- Jean-Laurent Casanova,
- Jean-Christophe Goffard,
- Savvas N. Savvides,
- Savvas N. Savvides,
- Filomeen Haerynck,
- Filomeen Haerynck,
- Jens Staal,
- Melissa Dullaers,
- Melissa Dullaers
Affiliations
- Marieke De Bruyne
- Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Marieke De Bruyne
- Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
- Marieke De Bruyne
- Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Levi Hoste
- Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Levi Hoste
- Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Delfien J. Bogaert
- Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Delfien J. Bogaert
- Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
- Delfien J. Bogaert
- Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Delfien J. Bogaert
- Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Lien Van den Bossche
- Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
- Lien Van den Bossche
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Simon J. Tavernier
- Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Simon J. Tavernier
- Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Eef Parthoens
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Eef Parthoens
- VIB Bioimaging Core, VIB, Ghent, Belgium
- Mélanie Migaud
- Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker Medical School, Imagine Institute, Paris Descartes University, Paris, France
- Deborah Konopnicki
- Infectious Diseases Department, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium
- Jean Cyr Yombi
- 0Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
- Bart N. Lambrecht
- Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Bart N. Lambrecht
- 1Department of Internal Medicine, Ghent University, Ghent, Belgium
- Sabine van Daele
- Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Ana Karina Alves de Medeiros
- 2Department of Dermatology, Ghent University Hospital, Ghent, Belgium
- Lieve Brochez
- 2Department of Dermatology, Ghent University Hospital, Ghent, Belgium
- Rudi Beyaert
- 3Unit of Molecular Signal Transduction in Inflammation, Department of Biomedical Molecular Biology, VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium
- Elfride De Baere
- Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
- Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker Medical School, Imagine Institute, Paris Descartes University, Paris, France
- Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker Medical School, Imagine Institute, Paris Descartes University, Paris, France
- Jean-Laurent Casanova
- 4St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, NY, United States; Pediatric Hematology-Immunology Unit, Necker Hospital, New York, NY, United States
- Jean-Christophe Goffard
- 5Immunodeficiency Unit, University Hospital ULB Erasme, Brussels, Belgium
- Savvas N. Savvides
- Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
- Savvas N. Savvides
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Filomeen Haerynck
- Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Filomeen Haerynck
- Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Jens Staal
- 3Unit of Molecular Signal Transduction in Inflammation, Department of Biomedical Molecular Biology, VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium
- Melissa Dullaers
- Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium
- Melissa Dullaers
- Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- DOI
- https://doi.org/10.3389/fimmu.2018.02366
- Journal volume & issue
-
Vol. 9
Abstract
Background: Inherited CARD9 deficiency constitutes a primary immunodeficiency predisposing uniquely to chronic and invasive fungal infections. Certain mutations are shown to negatively impact CARD9 protein expression and/or NF-κB activation, but the underlying biochemical mechanism remains to be fully understood.Objectives: To investigate a possible founder origin of a known CARD9 R70W mutation in five families of Turkish origin. To explore the biochemical mechanism of immunodeficiency by R70W CARD9.Methods: We performed haplotype analysis using microsatellite markers and SNPs. We designed a model system exploiting a gain-of-function (GOF) CARD9 L213LI mutant that triggers constitutive NF-κB activation, analogous to an oncogenic CARD11 mutant, to study NF-κB signaling and signalosome formation. We performed reporter assays, immunoprecipitation and confocal imaging on HEK cells overexpressing different CARD9 variants.Results: We identified a common haplotype, thus providing evidence for a common Turkish founder. CARD9 R70W failed to activate NF-κB and abrogated NF-κB activation by WT CARD9 and by GOF CARD9. Notably, R70W CARD9 also exerted negative effects on NF-κB activation by CARD10, CARD11, and CARD14. Consistent with the NF-κB results, the R70W mutation prevented GOF CARD9 to pull down the signalosome partner proteins BCL10 and MALT1. This reflected into drastic reduction of BCL10 filamentous assemblies in a cellular context. Indeed, structural analysis revealed that position R70 in CARD9 maps at the putative interface between successive CARD domains in CARD9 filaments.Conclusions: The R70W mutation in CARD9 prevents NF-κB activation by inhibiting productive interactions with downstream BCL10 and MALT1, necessary for assembly of the filamentous CARD9-BCL10-MALT1 signalosome.
Keywords
