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; 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.