Abstract |
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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Authors | Xin-Ming Jia, Bing Tang, Le-Le Zhu, Yan-Hui Liu, Xue-Qiang Zhao, Sara Gorjestani, Yen-Michael S Hsu, Long Yang, Jian-Hong Guan, Guo-Tong Xu, Xin Lin |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 211
Issue 11
Pg. 2307-21
(Oct 20 2014)
ISSN: 1540-9538 [Electronic] United States |
PMID | 25267792
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 Jia et al. |
Chemical References |
- CARD Signaling Adaptor Proteins
- CARD9 protein, human
- Lectins, C-Type
- Multiprotein Complexes
- NF-kappa B
- beta-Glucans
- dectin 1
- ras-GRF1
- Extracellular Signal-Regulated MAP Kinases
- ras Proteins
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Topics |
- Animals
- CARD Signaling Adaptor Proteins
(genetics, metabolism)
- Candida albicans
(drug effects, genetics, immunology)
- Candidiasis
(genetics, immunology, metabolism, mortality)
- Enzyme Activation
(drug effects)
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Female
- Fungi
(drug effects, genetics, immunology)
- Humans
- Immunity, Innate
- Lectins, C-Type
(genetics, metabolism)
- Mice
- Mice, Knockout
- Multiprotein Complexes
(metabolism)
- Mycoses
(genetics, immunology, metabolism, mortality)
- NF-kappa B
(metabolism)
- Protein Binding
- Signal Transduction
- beta-Glucans
(pharmacology)
- ras Proteins
(genetics, metabolism)
- ras-GRF1
(metabolism)
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