CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity.
CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity.
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DOI：
10.1084/jem.20132349
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发表时间：
2014-10-20
期刊：
影响因子：
--
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Jia XM;Tang B;Zhu LL;Liu YH;Zhao XQ;Gorjestani S;Hsu YM;Yang L;Guan JH;Xu GT;Lin X
在小鼠中，CARD 9对于由Dectin-1配体诱导的NF-κB活化是有效的。然而，Dectin-1诱导的H-Ras活化是由与CARD 9的复合物介导的，其导致ERK活化用于宿主对白色念珠菌感染的先天免疫应答。Dectin-1作为模式识别受体用于感知真菌感染。已经确定Dectin-1通过含有半胱天冬酶募集结构域的蛋白9（CARD 9）介导的NF-κB活化来诱导先天性免疫应答。在这项研究中，我们发现CARD 9是由Dectin-1配体诱导的NF-κB活化的抑制剂，例如可德兰或白色念珠菌酵母。相比之下，我们发现CARD 9通过将Ras-GRF 1连接到H-Ras来调节H-Ras活化，当被其配体刺激时，H-Ras介导Dectin-1诱导的细胞外信号调节蛋白激酶（ERK）活化和促炎反应。机制上，Dectin-1参与启动脾酪氨酸激酶（Syk）依赖性Ras-GRF 1磷酸化，磷酸化的Ras-GRF 1通过与CARD 9形成复合物募集并激活H-Ras，这导致下游ERK的激活。最后，我们发现，抑制ERK激活显着加速死亡的C。白色念珠菌感染的小鼠，并且这种抑制作用依赖于CARD 9。总之，我们的研究揭示了Dectin-1诱导H-Ras激活的分子机制，该机制导致ERK激活宿主对真菌感染的先天免疫应答。
CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands in mice. However, Dectin-1–induced H-Ras activation is mediated by a complex with CARD9, which leads to ERK activation for host innate immune responses to Candida albicans infection. Dectin-1 functions as a pattern recognition receptor for sensing fungal infection. It has been well-established that Dectin-1 induces innate immune responses through caspase recruitment domain-containing protein 9 (CARD9)–mediated NF-κB activation. In this study, we find that CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands, such as curdlan or Candida albicans yeast. In contrast, we find that CARD9 regulates H-Ras activation by linking Ras-GRF1 to H-Ras, which mediates Dectin-1–induced extracellular signal-regulated protein kinase (ERK) activation and proinflammatory responses when stimulated by their ligands. Mechanistically, Dectin-1 engagement initiates spleen tyrosine kinase (Syk)–dependent Ras-GRF1 phosphorylation, and the phosphorylated Ras-GRF1 recruits and activates H-Ras through forming a complex with CARD9, which leads to activation of ERK downstream. Finally, we show that inhibiting ERK activation significantly accelerates the death of C. albicans–infected mice, and this inhibitory effect is dependent on CARD9. Together, our studies reveal a molecular mechanism by which Dectin-1 induces H-Ras activation that leads to ERK activation for host innate immune responses against fungal infection.
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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：
15.9
作者：
Dillon, S;Agrawal, S;Pulendran, B
通讯作者：
Pulendran, B
影响因子：
30.5
作者：
Gringhuis, Sonja I.;den Dunnen, Jeroen;Geijtenbeek, Teunis B. H.
通讯作者：
Geijtenbeek, Teunis B. H.
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