title: 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.affiliation: 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.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Jia
authors.affiliation: Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Tang
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Le-Le
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Xue-Qiang
authors.initials: XQ
authors.lastname: Zhao
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Sara
authors.initials: S
authors.lastname: Gorjestani
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Yen-Michael S
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Long
authors.initials: L
authors.lastname: Yang
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Guan
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Guo-Tong
authors.initials: GT
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 jiaxm@tongji.edu.cn xllin@mdanderson.org.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002177:Candidiasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005658:Fungi / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009181:Mycoses / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D047071:beta-Glucans / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D020666:ras-GRF1 / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D037181:Lectins, C-Type; D046912:Multiprotein Complexes; D016328:NF-kappa B; D047071:beta-Glucans; D018631:ras Proteins; D020666:ras-GRF1; D000099181:Dectin-1; C505855:CARD9 protein, human