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

• Published in: The Journal of experimental medicine Vol. 211; no. 11; pp. 2307 - 2321
• Main Authors: Jia, Xin-Ming, Tang, Bing, Zhu, Le-Le, Liu, Yan-Hui, Zhao, Xue-Qiang, Gorjestani, Sara, Hsu, Yen-Michael S, Yang, Long, Guan, Jian-Hong, Xu, Guo-Tong, Lin, Xin
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 20-10-2014
• Subjects: Animals; beta-Glucans - pharmacology; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candida albicans - immunology; Candidiasis - genetics; Candidiasis - immunology; Candidiasis - metabolism; Candidiasis - mortality; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Enzyme Activation - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fungi - drug effects; Fungi - genetics; Fungi - immunology; Humans; Immunity, Innate; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Mice; Mice, Knockout; Multiprotein Complexes - metabolism; Mycoses - genetics; Mycoses - immunology; Mycoses - metabolism; Mycoses - mortality; NF-kappa B - metabolism; Protein Binding; ras Proteins - genetics; ras Proteins - metabolism; ras-GRF1 - metabolism; Signal Transduction
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20132349

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.