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Front Immunol. 2018 Oct 31;9:2366. doi: 10.3389/fimmu.2018.02366. eCollection 2018.

A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation.

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Primary Immunodeficiency Research Lab, Department of Pulmonary Medicine, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium.
Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiencies, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium.
Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
VIB-UGent Center for Inflammation Research, Ghent, Belgium.
VIB Bioimaging Core, VIB, Ghent, Belgium.
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker Medical School, Imagine Institute, Paris Descartes University, Paris, France.
Infectious Diseases Department, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium.
Department of Internal Medicine, Ghent University, Ghent, Belgium.
Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
Unit of Molecular Signal Transduction in Inflammation, Department of Biomedical Molecular Biology, VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium.
St 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.
Immunodeficiency Unit, University Hospital ULB Erasme, Brussels, Belgium.


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.


BCL10; CARD9 deficiency; CBM complex; MALT1; NF-κB; filament; founder mutation; signalosome

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