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

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 ful...
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Autor*in:	Marieke De Bruyne [verfasserIn] Levi Hoste [verfasserIn] Delfien J. Bogaert [verfasserIn] Lien Van den Bossche [verfasserIn] Simon J. Tavernier [verfasserIn] Eef Parthoens [verfasserIn] Mélanie Migaud [verfasserIn] Deborah Konopnicki [verfasserIn] Jean Cyr Yombi [verfasserIn] Bart N. Lambrecht [verfasserIn] Sabine van Daele [verfasserIn] Ana Karina Alves de Medeiros [verfasserIn] Lieve Brochez [verfasserIn] Rudi Beyaert [verfasserIn] Elfride De Baere [verfasserIn] Anne Puel [verfasserIn] Jean-Laurent Casanova [verfasserIn] Jean-Christophe Goffard [verfasserIn] Savvas N. Savvides [verfasserIn] Filomeen Haerynck [verfasserIn] Jens Staal [verfasserIn] Melissa Dullaers [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB

Übergeordnetes Werk:	In: Frontiers in Immunology - Frontiers Media S.A., 2011, 9(2018)
Übergeordnetes Werk:	volume:9 ; year:2018

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fimmu.2018.02366

Katalog-ID:	DOAJ005828023

Internformat


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100	0		\|a Marieke De Bruyne \|e verfasserin \|4 aut
245	1	2	\|a A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
264		1	\|c 2018
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
520			\|a 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.
650		4	\|a CARD9 deficiency
650		4	\|a founder mutation
650		4	\|a BCL10
650		4	\|a MALT1
650		4	\|a CBM complex
650		4	\|a NF-κB
653		0	\|a Immunologic diseases. Allergy
700	0		\|a Marieke De Bruyne \|e verfasserin \|4 aut
700	0		\|a Marieke De Bruyne \|e verfasserin \|4 aut
700	0		\|a Levi Hoste \|e verfasserin \|4 aut
700	0		\|a Levi Hoste \|e verfasserin \|4 aut
700	0		\|a Delfien J. Bogaert \|e verfasserin \|4 aut
700	0		\|a Delfien J. Bogaert \|e verfasserin \|4 aut
700	0		\|a Delfien J. Bogaert \|e verfasserin \|4 aut
700	0		\|a Delfien J. Bogaert \|e verfasserin \|4 aut
700	0		\|a Lien Van den Bossche \|e verfasserin \|4 aut
700	0		\|a Lien Van den Bossche \|e verfasserin \|4 aut
700	0		\|a Simon J. Tavernier \|e verfasserin \|4 aut
700	0		\|a Simon J. Tavernier \|e verfasserin \|4 aut
700	0		\|a Eef Parthoens \|e verfasserin \|4 aut
700	0		\|a Eef Parthoens \|e verfasserin \|4 aut
700	0		\|a Mélanie Migaud \|e verfasserin \|4 aut
700	0		\|a Deborah Konopnicki \|e verfasserin \|4 aut
700	0		\|a Jean Cyr Yombi \|e verfasserin \|4 aut
700	0		\|a Bart N. Lambrecht \|e verfasserin \|4 aut
700	0		\|a Bart N. Lambrecht \|e verfasserin \|4 aut
700	0		\|a Sabine van Daele \|e verfasserin \|4 aut
700	0		\|a Ana Karina Alves de Medeiros \|e verfasserin \|4 aut
700	0		\|a Lieve Brochez \|e verfasserin \|4 aut
700	0		\|a Rudi Beyaert \|e verfasserin \|4 aut
700	0		\|a Elfride De Baere \|e verfasserin \|4 aut
700	0		\|a Anne Puel \|e verfasserin \|4 aut
700	0		\|a Jean-Laurent Casanova \|e verfasserin \|4 aut
700	0		\|a Jean-Laurent Casanova \|e verfasserin \|4 aut
700	0		\|a Jean-Christophe Goffard \|e verfasserin \|4 aut
700	0		\|a Savvas N. Savvides \|e verfasserin \|4 aut
700	0		\|a Savvas N. Savvides \|e verfasserin \|4 aut
700	0		\|a Filomeen Haerynck \|e verfasserin \|4 aut
700	0		\|a Filomeen Haerynck \|e verfasserin \|4 aut
700	0		\|a Jens Staal \|e verfasserin \|4 aut
700	0		\|a Melissa Dullaers \|e verfasserin \|4 aut
700	0		\|a Melissa Dullaers \|e verfasserin \|4 aut
773	0	8	\|i In \|t Frontiers in Immunology \|d Frontiers Media S.A., 2011 \|g 9(2018) \|w (DE-627)657998354 \|w (DE-600)2606827-8 \|x 16643224 \|7 nnns
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856	4	2	\|u https://doaj.org/toc/1664-3224 \|y Journal toc \|z kostenfrei
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912			\|a GBV_ILN_293
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912			\|a GBV_ILN_2003
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912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
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Indexfelder

author_variant	m d b mdb m d b mdb m d b mdb l h lh l h lh d j b djb d j b djb d j b djb d j b djb l v d b lvdb l v d b lvdb s j t sjt s j t sjt e p ep e p ep m m mm d k dk j c y jcy b n l bnl b n l bnl s v d svd a k a d m akadm l b lb r b rb e d b edb a p ap j l c jlc j l c jlc j c g jcg s n s sns s n s sns f h fh f h fh j s js m d md m d md
matchkey_str	article:16643224:2018----::cr9onemttodsutnbinlnbihbtnbl0nml1erim
hierarchy_sort_str	2018
callnumber-subject-code	RC
publishDate	2018
allfields	10.3389/fimmu.2018.02366 doi (DE-627)DOAJ005828023 (DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f DE-627 ger DE-627 rakwb eng RC581-607 Marieke De Bruyne verfasserin aut A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB Immunologic diseases. Allergy Marieke De Bruyne verfasserin aut Marieke De Bruyne verfasserin aut Levi Hoste verfasserin aut Levi Hoste verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Lien Van den Bossche verfasserin aut Lien Van den Bossche verfasserin aut Simon J. Tavernier verfasserin aut Simon J. Tavernier verfasserin aut Eef Parthoens verfasserin aut Eef Parthoens verfasserin aut Mélanie Migaud verfasserin aut Deborah Konopnicki verfasserin aut Jean Cyr Yombi verfasserin aut Bart N. Lambrecht verfasserin aut Bart N. Lambrecht verfasserin aut Sabine van Daele verfasserin aut Ana Karina Alves de Medeiros verfasserin aut Lieve Brochez verfasserin aut Rudi Beyaert verfasserin aut Elfride De Baere verfasserin aut Anne Puel verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Christophe Goffard verfasserin aut Savvas N. Savvides verfasserin aut Savvas N. Savvides verfasserin aut Filomeen Haerynck verfasserin aut Filomeen Haerynck verfasserin aut Jens Staal verfasserin aut Melissa Dullaers verfasserin aut Melissa Dullaers verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.02366 kostenfrei https://doaj.org/article/0ba87f23952c42b5b2b177471ecb035f kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2018.02366/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018
spelling	10.3389/fimmu.2018.02366 doi (DE-627)DOAJ005828023 (DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f DE-627 ger DE-627 rakwb eng RC581-607 Marieke De Bruyne verfasserin aut A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB Immunologic diseases. Allergy Marieke De Bruyne verfasserin aut Marieke De Bruyne verfasserin aut Levi Hoste verfasserin aut Levi Hoste verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Lien Van den Bossche verfasserin aut Lien Van den Bossche verfasserin aut Simon J. Tavernier verfasserin aut Simon J. Tavernier verfasserin aut Eef Parthoens verfasserin aut Eef Parthoens verfasserin aut Mélanie Migaud verfasserin aut Deborah Konopnicki verfasserin aut Jean Cyr Yombi verfasserin aut Bart N. Lambrecht verfasserin aut Bart N. Lambrecht verfasserin aut Sabine van Daele verfasserin aut Ana Karina Alves de Medeiros verfasserin aut Lieve Brochez verfasserin aut Rudi Beyaert verfasserin aut Elfride De Baere verfasserin aut Anne Puel verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Christophe Goffard verfasserin aut Savvas N. Savvides verfasserin aut Savvas N. Savvides verfasserin aut Filomeen Haerynck verfasserin aut Filomeen Haerynck verfasserin aut Jens Staal verfasserin aut Melissa Dullaers verfasserin aut Melissa Dullaers verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.02366 kostenfrei https://doaj.org/article/0ba87f23952c42b5b2b177471ecb035f kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2018.02366/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018
allfields_unstemmed	10.3389/fimmu.2018.02366 doi (DE-627)DOAJ005828023 (DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f DE-627 ger DE-627 rakwb eng RC581-607 Marieke De Bruyne verfasserin aut A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB Immunologic diseases. Allergy Marieke De Bruyne verfasserin aut Marieke De Bruyne verfasserin aut Levi Hoste verfasserin aut Levi Hoste verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Lien Van den Bossche verfasserin aut Lien Van den Bossche verfasserin aut Simon J. Tavernier verfasserin aut Simon J. Tavernier verfasserin aut Eef Parthoens verfasserin aut Eef Parthoens verfasserin aut Mélanie Migaud verfasserin aut Deborah Konopnicki verfasserin aut Jean Cyr Yombi verfasserin aut Bart N. Lambrecht verfasserin aut Bart N. Lambrecht verfasserin aut Sabine van Daele verfasserin aut Ana Karina Alves de Medeiros verfasserin aut Lieve Brochez verfasserin aut Rudi Beyaert verfasserin aut Elfride De Baere verfasserin aut Anne Puel verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Christophe Goffard verfasserin aut Savvas N. Savvides verfasserin aut Savvas N. Savvides verfasserin aut Filomeen Haerynck verfasserin aut Filomeen Haerynck verfasserin aut Jens Staal verfasserin aut Melissa Dullaers verfasserin aut Melissa Dullaers verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.02366 kostenfrei https://doaj.org/article/0ba87f23952c42b5b2b177471ecb035f kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2018.02366/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018
allfieldsGer	10.3389/fimmu.2018.02366 doi (DE-627)DOAJ005828023 (DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f DE-627 ger DE-627 rakwb eng RC581-607 Marieke De Bruyne verfasserin aut A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB Immunologic diseases. Allergy Marieke De Bruyne verfasserin aut Marieke De Bruyne verfasserin aut Levi Hoste verfasserin aut Levi Hoste verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Lien Van den Bossche verfasserin aut Lien Van den Bossche verfasserin aut Simon J. Tavernier verfasserin aut Simon J. Tavernier verfasserin aut Eef Parthoens verfasserin aut Eef Parthoens verfasserin aut Mélanie Migaud verfasserin aut Deborah Konopnicki verfasserin aut Jean Cyr Yombi verfasserin aut Bart N. Lambrecht verfasserin aut Bart N. Lambrecht verfasserin aut Sabine van Daele verfasserin aut Ana Karina Alves de Medeiros verfasserin aut Lieve Brochez verfasserin aut Rudi Beyaert verfasserin aut Elfride De Baere verfasserin aut Anne Puel verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Christophe Goffard verfasserin aut Savvas N. Savvides verfasserin aut Savvas N. Savvides verfasserin aut Filomeen Haerynck verfasserin aut Filomeen Haerynck verfasserin aut Jens Staal verfasserin aut Melissa Dullaers verfasserin aut Melissa Dullaers verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.02366 kostenfrei https://doaj.org/article/0ba87f23952c42b5b2b177471ecb035f kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2018.02366/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018
allfieldsSound	10.3389/fimmu.2018.02366 doi (DE-627)DOAJ005828023 (DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f DE-627 ger DE-627 rakwb eng RC581-607 Marieke De Bruyne verfasserin aut A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB Immunologic diseases. Allergy Marieke De Bruyne verfasserin aut Marieke De Bruyne verfasserin aut Levi Hoste verfasserin aut Levi Hoste verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Delfien J. Bogaert verfasserin aut Lien Van den Bossche verfasserin aut Lien Van den Bossche verfasserin aut Simon J. Tavernier verfasserin aut Simon J. Tavernier verfasserin aut Eef Parthoens verfasserin aut Eef Parthoens verfasserin aut Mélanie Migaud verfasserin aut Deborah Konopnicki verfasserin aut Jean Cyr Yombi verfasserin aut Bart N. Lambrecht verfasserin aut Bart N. Lambrecht verfasserin aut Sabine van Daele verfasserin aut Ana Karina Alves de Medeiros verfasserin aut Lieve Brochez verfasserin aut Rudi Beyaert verfasserin aut Elfride De Baere verfasserin aut Anne Puel verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Laurent Casanova verfasserin aut Jean-Christophe Goffard verfasserin aut Savvas N. Savvides verfasserin aut Savvas N. Savvides verfasserin aut Filomeen Haerynck verfasserin aut Filomeen Haerynck verfasserin aut Jens Staal verfasserin aut Melissa Dullaers verfasserin aut Melissa Dullaers verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.02366 kostenfrei https://doaj.org/article/0ba87f23952c42b5b2b177471ecb035f kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2018.02366/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018
language	English
source	In Frontiers in Immunology 9(2018) volume:9 year:2018
sourceStr	In Frontiers in Immunology 9(2018) volume:9 year:2018
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB Immunologic diseases. Allergy
isfreeaccess_bool	true
container_title	Frontiers in Immunology
authorswithroles_txt_mv	Marieke De Bruyne @@aut@@ Levi Hoste @@aut@@ Delfien J. Bogaert @@aut@@ Lien Van den Bossche @@aut@@ Simon J. Tavernier @@aut@@ Eef Parthoens @@aut@@ Mélanie Migaud @@aut@@ Deborah Konopnicki @@aut@@ Jean Cyr Yombi @@aut@@ Bart N. Lambrecht @@aut@@ Sabine van Daele @@aut@@ Ana Karina Alves de Medeiros @@aut@@ Lieve Brochez @@aut@@ Rudi Beyaert @@aut@@ Elfride De Baere @@aut@@ Anne Puel @@aut@@ Jean-Laurent Casanova @@aut@@ Jean-Christophe Goffard @@aut@@ Savvas N. Savvides @@aut@@ Filomeen Haerynck @@aut@@ Jens Staal @@aut@@ Melissa Dullaers @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	657998354
id	DOAJ005828023
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ005828023</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230309194530.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230225s2018 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3389/fimmu.2018.02366</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ005828023</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC581-607</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Marieke De Bruyne</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CARD9 deficiency</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">founder mutation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BCL10</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">MALT1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CBM complex</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">NF-κB</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Immunologic diseases. 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callnumber-first	R - Medicine
author	Marieke De Bruyne
spellingShingle	Marieke De Bruyne misc RC581-607 misc CARD9 deficiency misc founder mutation misc BCL10 misc MALT1 misc CBM complex misc NF-κB misc Immunologic diseases. Allergy A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
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topic_title	RC581-607 A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation CARD9 deficiency founder mutation BCL10 MALT1 CBM complex NF-κB
topic	misc RC581-607 misc CARD9 deficiency misc founder mutation misc BCL10 misc MALT1 misc CBM complex misc NF-κB misc Immunologic diseases. Allergy
topic_unstemmed	misc RC581-607 misc CARD9 deficiency misc founder mutation misc BCL10 misc MALT1 misc CBM complex misc NF-κB misc Immunologic diseases. Allergy
topic_browse	misc RC581-607 misc CARD9 deficiency misc founder mutation misc BCL10 misc MALT1 misc CBM complex misc NF-κB misc Immunologic diseases. Allergy
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title	A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
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title_full	A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
author_sort	Marieke De Bruyne
journal	Frontiers in Immunology
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author_browse	Marieke De Bruyne Levi Hoste Delfien J. Bogaert Lien Van den Bossche Simon J. Tavernier Eef Parthoens Mélanie Migaud Deborah Konopnicki Jean Cyr Yombi Bart N. Lambrecht Sabine van Daele Ana Karina Alves de Medeiros Lieve Brochez Rudi Beyaert Elfride De Baere Anne Puel Jean-Laurent Casanova Jean-Christophe Goffard Savvas N. Savvides Filomeen Haerynck Jens Staal Melissa Dullaers
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author-letter	Marieke De Bruyne
doi_str_mv	10.3389/fimmu.2018.02366
author2-role	verfasserin
title_sort	card9 founder mutation disrupts nf-κb signaling by inhibiting bcl10 and malt1 recruitment and signalosome formation
callnumber	RC581-607
title_auth	A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation
url	https://doi.org/10.3389/fimmu.2018.02366 https://doaj.org/article/0ba87f23952c42b5b2b177471ecb035f https://www.frontiersin.org/article/10.3389/fimmu.2018.02366/full https://doaj.org/toc/1664-3224
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author2	Marieke De Bruyne Levi Hoste Delfien J. Bogaert Lien Van den Bossche Simon J. Tavernier Eef Parthoens Mélanie Migaud Deborah Konopnicki Jean Cyr Yombi Bart N. Lambrecht Sabine van Daele Ana Karina Alves de Medeiros Lieve Brochez Rudi Beyaert Elfride De Baere Anne Puel Jean-Laurent Casanova Jean-Christophe Goffard Savvas N. Savvides Filomeen Haerynck Jens Staal Melissa Dullaers
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up_date	2024-07-03T17:21:26.696Z
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ005828023</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230309194530.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230225s2018 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3389/fimmu.2018.02366</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ005828023</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ0ba87f23952c42b5b2b177471ecb035f</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC581-607</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Marieke De Bruyne</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CARD9 deficiency</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">founder mutation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BCL10</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">MALT1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CBM complex</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">NF-κB</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Immunologic diseases. 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A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation

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