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

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.

• 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)
• 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

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)