A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation.
A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation.
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DOI：
10.3389/fimmu.2018.02366
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发表时间：
2018
影响因子：
7.3
通讯作者：
Dullaers M
中科院分区：
文献类型：
--
作者：
De Bruyne M;Hoste L;Bogaert DJ;Van den Bossche L;Tavernier SJ;Parthoens E;Migaud M;Konopnicki D;Yombi JC;Lambrecht BN;van Daele S;Alves de Medeiros AK;Brochez L;Beyaert R;De Baere E;Puel A;Casanova JL;Goffard JC;Savvides SN;Haerynck F;Staal J;Dullaers M
背景：遗传性CARD9缺陷是一种易患慢性侵袭性真菌感染的原发免疫缺陷。某些突变被证明对CARD9蛋白表达和/或NF-κB激活产生负面影响，但其潜在的生化机制仍未完全清楚。目的：研究土耳其血统5个家系中已知的CARD9 R70W突变的可能创始人来源。探讨R70W CARD9免疫缺陷的生化机制。方法：利用微卫星标记和SNPs进行单倍型分析。我们设计了一个模型系统，利用一个功能增益(GOF)CARD9L213LI突变体来研究NF-κB信号和信号体的形成。该突变体类似于癌基因CARD11突变体，可以触发结构性的NF-κB激活。我们对过度表达不同CARD9变异体的HEK细胞进行了报告分析、免疫沉淀和共聚焦成像。结果：我们确定了一个共同的单倍型，从而为共同的土耳其创始人提供了证据。CARD9R70W不能激活NF-κB，WT CARD9和GOF CARD9均能抑制NF-κB的激活。值得注意的是，R70W CARD9还对CARD10、CARD11和CARD14激活的NF-κB产生负面影响。与NF-κB的结果一致，R70W突变阻止了GOF CARD9下调信号体伙伴蛋白Bcl10和MALT1。这反映在细胞环境中Bcl10丝状组件的急剧减少。事实上，结构分析表明，CARD9中的R70位置映射到CARD9细丝中连续的卡片域之间的假定界面。结论：CARD9R70W突变通过抑制与下游Bcl10和MALT1的生产性相互作用来阻止NF-κB的激活，MALT1是组装丝状CARD9-Bcl10-MALT1信号体所必需的。
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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对C型凝集素受体/Card9信号在人类抗真菌免疫中的作用的机械洞察力。
影响因子：
5.7
作者：
Drummond RA;Lionakis MS
通讯作者：
Lionakis MS
DOI：
10.1056/nejmoa1208487
发表时间：
2013-10-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lanternier F;Pathan S;Vincent QB;Liu L;Cypowyj S;Prando C;Migaud M;Taibi L;Ammar-Khodja A;Stambouli OB;Guellil B;Jacobs F;Goffard JC;Schepers K;Del Marmol V;Boussofara L;Denguezli M;Larif M;Bachelez H;Michel L;Lefranc G;Hay R;Jouvion G;Chretien F;Fraitag S;Bougnoux ME;Boudia M;Abel L;Lortholary O;Casanova JL;Picard C;Grimbacher B;Puel A
通讯作者：
Puel A
影响因子：
56.9
作者：
Lenz, Georg;Davis, R. Eric;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
64.8
作者：
Gross, Olaf;Gewies, Andreas;Ruland, Juergen
通讯作者：
Ruland, Juergen
影响因子：
4.8
作者：
Bertin, J;Guo, Y;Alnemri, ES
通讯作者：
Alnemri, ES