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J Exp Med. 2014 Oct 20;211(11):2307-21. doi: 10.1084/jem.20132349. Epub 2014 Sep 29.

CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity.

Author information

1
Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China jiaxm@tongji.edu.cn xllin@mdanderson.org.
2
Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
3
Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China.
4
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
5
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 jiaxm@tongji.edu.cn xllin@mdanderson.org.

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.

PMID:
25267792
PMCID:
PMC4203953
DOI:
10.1084/jem.20132349
[Indexed for MEDLINE]
Free PMC Article

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