The scaffold protein CARD9 plays an essential role in anti-fungus immunity and is implicated in mediating Dectin-1/Syk-induced NF-κB activation in response to Candida albicans infection. However, the molecular mechanism by which CARD9 mediates C. albicans-induced NF-κB activation is not fully characterized. Here we demonstrate that CARD9 is involved in mediating NF-κB activation induced by the hyphal form of C. albicans hyphae (Hyphae) but not by its heat-inactivated unicellular form. Our data show that inhibiting Dectin-2 expression selectively blocked Hyphae-induced NF-κB, whereas inhibiting Dectin-1 mainly suppressed zymosan-induced NF-κB, indicating that Hyphae-induced NF-κB activation is mainly through Dectin-2 and not Dectin-1. Consistently, we find that the hyphae stimulation induces CARD9 association with Bcl10, an adaptor protein that functions downstream of CARD9 and is also involved in C. albicans-induced NF-κB activation. This association is dependent on Dectin-2 but not Dectin-1 following the hyphae stimulation. Finally, we find that although both CARD9 and Syk are required for Hyphae-induced NF-κB activation, they regulate different signaling events in which CARD9 mediates IκBα kinase ubiquitination, whereas Syk regulates IκBα kinase phosphorylation. Together, our data demonstrated that CARD9 is selectively involved in Dectin-2-induced NF-κB activation in response to C. albicans hyphae challenging. The scaffold protein CARD9 plays an essential role in anti-fungus immunity and is implicated in mediating Dectin-1/Syk-induced NF-κB activation in response to Candida albicans infection. However, the molecular mechanism by which CARD9 mediates C. albicans-induced NF-κB activation is not fully characterized. Here we demonstrate that CARD9 is involved in mediating NF-κB activation induced by the hyphal form of C. albicans hyphae (Hyphae) but not by its heat-inactivated unicellular form. Our data show that inhibiting Dectin-2 expression selectively blocked Hyphae-induced NF-κB, whereas inhibiting Dectin-1 mainly suppressed zymosan-induced NF-κB, indicating that Hyphae-induced NF-κB activation is mainly through Dectin-2 and not Dectin-1. Consistently, we find that the hyphae stimulation induces CARD9 association with Bcl10, an adaptor protein that functions downstream of CARD9 and is also involved in C. albicans-induced NF-κB activation. This association is dependent on Dectin-2 but not Dectin-1 following the hyphae stimulation. Finally, we find that although both CARD9 and Syk are required for Hyphae-induced NF-κB activation, they regulate different signaling events in which CARD9 mediates IκBα kinase ubiquitination, whereas Syk regulates IκBα kinase phosphorylation. Together, our data demonstrated that CARD9 is selectively involved in Dectin-2-induced NF-κB activation in response to C. albicans hyphae challenging. IntroductionCandida albicans is a major opportunistic fungal pathogen that predominantly causes infection to cancer patients and immunocompromised individuals. During C. albicans infection, macrophages and dendritic cells recognize components from the fungal cell wall through their pattern recognition receptors (1Netea M.G. Brown G.D. Kullberg B.J. Gow N.A. Nat. Rev. Microbiol. 2008; 6: 67-78Crossref PubMed Scopus (686) Google Scholar, 2Robinson M.J. Sancho D. Slack E.C. LeibundGut-Landmann S. Reis e Sousa C. Nat. Immunol. 2006; 7: 1258-1265Crossref PubMed Scopus (421) Google Scholar), which triggers a series of signaling cascades leading to activation of various transcription factors including NF-κB (1Netea M.G. Brown G.D. Kullberg B.J. Gow N.A. Nat. Rev. Microbiol. 2008; 6: 67-78Crossref PubMed Scopus (686) Google Scholar). The activation of NF-κB and other transcription factors further induce the expression of various cytokines and chemokines and inflammatory responses. However, the pattern recognition receptors that recognize fungal cell wall components are not fully defined (3Willment J.A. Brown G.D. Trends Microbiol. 2008; 16: 27-32Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar).NF-κB is a family of transcription factors that control the expression of pro-inflammatory genes in immune cells (4Hayden M.S. Ghosh S. Cell. 2008; 132: 344-362Abstract Full Text Full Text PDF PubMed Scopus (3447) Google Scholar). In resting cells, the activity of NF-κB is tightly controlled by the IκB family of proteins, which bind to NF-κB dimers and keep these dimers in the cytoplasm. The canonical NF-κB activation pathway by most of NF-κB-inducing stimuli activates the IκBα kinase (IKK) 2The abbreviations used are: IKKIκBα kinaseTLRToll-like receptorLPSlipopolysaccharideERKextracellular signal-regulated kinaseBMDMbone marrow-derived macrophageshRNAsmall hairpin RNAILinterleukinEMSAelectrophoretic mobility shift assayMOImultiplicity of infection. complex. The IKK complex is controlled by signal-induced phosphorylation of IKKα and IKKβ subunits (5Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4046) Google Scholar) and signal-induced K63-linked ubiquitination of the regulatory subunit NEMO (6Chen Z.J. Nat. Cell Biol. 2005; 7: 758-765Crossref PubMed Scopus (1009) Google Scholar). The activated IKK complex in turn phosphorylates IκBα proteins on N-terminal conserved serine residues to target them for ubiquitination-dependent degradation (5Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4046) Google Scholar). This process releases NF-κB and allows its translocation into the nucleus for the activation of its target genes (4Hayden M.S. Ghosh S. Cell. 2008; 132: 344-362Abstract Full Text Full Text PDF PubMed Scopus (3447) Google Scholar). Although it has been shown that bacterial and viral infections induce IKK activation by Toll-like receptors (TLRs), the molecular mechanism by which fungal infection induces NF-κB activation is not fully defined.Dectin-1 is a glycosylated type II transmembrane receptor and is mainly expressed in myeloid cells (7Ariizumi K. Shen G.L. Shikano S. Xu S. Ritter 3rd, R. Kumamoto T. Edelbaum D. Morita A. Bergstresser P.R. Takashima A. J. Biol. Chem. 2000; 275: 20157-20167Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar). It contains a single extracellular C-type lectin-like domain and a cytoplasmic domain containing an immunoreceptor tyrosine-based activation-like motif (7Ariizumi K. Shen G.L. Shikano S. Xu S. Ritter 3rd, R. Kumamoto T. Edelbaum D. Morita A. Bergstresser P.R. Takashima A. J. Biol. Chem. 2000; 275: 20157-20167Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 8Reid D.M. Gow N.A. Brown G.D. Curr. Opin. Immunol. 2009; 21: 30-37Crossref PubMed Scopus (217) Google Scholar). The ligand for Dectin-1 is β-glucan (9Brown G.D. Taylor P.R. Reid D.M. Willment J.A. Williams D.L. Martinez-Pomares L. Wong S.Y. Gordon S. J. Exp. Med. 2002; 196: 407-412Crossref PubMed Scopus (797) Google Scholar,10Brown G.D. Herre J. Williams D.L. Willment J.A. Marshall A.S. Gordon S. J. Exp. Med. 2003; 197: 1119-1124Crossref PubMed Scopus (983) Google Scholar), a carbohydrate found in the cell wall of plant and fungi. Upon binding to β-glucan, Dectin-1 recruits and activates Syk (11Underhill D.M. Rossnagle E. Lowell C.A. Simmons R.M. Blood. 2005; 106: 2543-2550Crossref PubMed Scopus (401) Google Scholar, 12Rogers N.C. Slack E.C. Edwards A.D. Nolte M.A. Schulz O. Schweighoffer E. Williams D.L. Gordon S. Tybulewicz V.L. Brown G.D. Reis e Sousa C. Immunity. 2005; 22: 507-517Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar), an intracellular tyrosine kinase, through its immunoreceptor tyrosine-based activation-like motif, which triggers several intracellular signaling cascades leading to induction of various cytokines (10Brown G.D. Herre J. Williams D.L. Willment J.A. Marshall A.S. Gordon S. J. Exp. Med. 2003; 197: 1119-1124Crossref PubMed Scopus (983) Google Scholar, 13Gantner B.N. Simmons R.M. Canavera S.J. Akira S. Underhill D.M. J. Exp. Med. 2003; 197: 1107-1117Crossref PubMed Scopus (1309) Google Scholar, 14Gantner B.N. Simmons R.M. Underhill D.M. EMBO J. 2005; 24: 1277-1286Crossref PubMed Scopus (503) Google Scholar). In addition, it has been shown that Dectin-1 collaborates with TLRs to activate inflammatory responses following fungal infection (14Gantner B.N. Simmons R.M. Underhill D.M. EMBO J. 2005; 24: 1277-1286Crossref PubMed Scopus (503) Google Scholar). Therefore, it has been proposed that Dectin-1 functions as a pattern recognition receptor for fungal infection and mediates anti-fungus immune responses (8Reid D.M. Gow N.A. Brown G.D. Curr. Opin. Immunol. 2009; 21: 30-37Crossref PubMed Scopus (217) Google Scholar, 14Gantner B.N. Simmons R.M. Underhill D.M. EMBO J. 2005; 24: 1277-1286Crossref PubMed Scopus (503) Google Scholar, 15Brown G.D. Nat. Rev. 2006; 6: 33-43Google Scholar). Although the definite role of Dectin-1 in anti-fungus immunity remains to be fully determined (16Saijo S. Fujikado N. Furuta T. Chung S.H. Kotaki H. Seki K. Sudo K. Akira S. Adachi Y. Ohno N. Kinjo T. Nakamura K. Kawakami K. Iwakura Y. Nat. Immunol. 2007; 8: 39-46Crossref PubMed Scopus (511) Google Scholar, 17Taylor P.R. Tsoni S.V. Willment J.A. Dennehy K.M. Rosas M. Findon H. Haynes K. Steele C. Botto M. Gordon S. Brown G.D. Nat. Immunol. 2007; 8: 31-38Crossref PubMed Scopus (880) Google Scholar), the deficiency in human Dectin-1 expression results in a defect of mucosal anti-fungal defense (18Ferwerda B. Ferwerda G. Plantinga T.S. Willment J.A. van Spriel A.B. Venselaar H. Elbers C.C. Johnson M.D. Cambi A. Huysamen C. Jacobs L. Jansen T. Verheijen K. Masthoff L. Morré S.A. Vriend G. Williams D.L. Perfect J.R. Joosten L.A. Wijmenga C. van der Meer J.W. Adema G.J. Kullberg B.J. Brown G.D. Netea M.G. New Engl. J. Med. 2009; 361: 1760-1767Crossref PubMed Scopus (588) Google Scholar). In addition, it has been shown that β-glucan on the surface of C. albicans is predominantly buried beneath a monoprotein coat upon C. albicans into its hyphal form the infection 2006; PubMed Scopus Google Scholar). Therefore, the β-glucan on the cell wall of C. albicans is for the that the immunity is also induced by other components β-glucan on the surface of C. is C-type lectin-like receptor and is expressed in myeloid cells K. Shen G.L. Shikano S. Ritter 3rd, R. Edelbaum D. Morita A. Takashima A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). In to Dectin-2 not an immunoreceptor tyrosine-based activation-like motif in its cytoplasmic K. Shen G.L. Shikano S. Ritter 3rd, R. Edelbaum D. Morita A. Takashima A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Brown G.D. 2009; PubMed Scopus Google Scholar). The extracellular domain of Dectin-2 to for as and Rosas M. Brown G.D. S. Wong S.Y. Gordon S. Martinez-Pomares L. Taylor P.R. 2006; 16: PubMed Scopus Google Scholar), that these be the ligand for It has been that Dectin-2 recruits intracellular signaling leading to activation of NF-κB upon the hyphal form of C. albicans K. T. Chung J. K. Underhill D. K. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Rosas M. Schweighoffer E. O. J. Tybulewicz Brown G.D. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; PubMed Scopus Google Scholar). However, the molecular mechanism by which Dectin-2 mediates anti-fungus immunity is not fully characterized. In addition, the ligand for Dectin-2 and the signaling pathway induced by Dectin-2 to be is an adaptor protein that contains an N-terminal domain and a domain and is mainly expressed in myeloid cells J. Y. L. M.D. S. M.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Y. D. H. O. C. Nat. Immunol. 2007; 8: PubMed Scopus Google Scholar). demonstrate that CARD9 plays bacterial and fungal infection, and are to and C. albicans infection Y. Y. D. H. O. C. Nat. Immunol. 2007; 8: PubMed Scopus Google Scholar, O. A. K. M. T. C. J. 2006; PubMed Scopus Google Scholar, H. C. A. T. L. M. T. A. S. Iwakura Y. Ohno N. H. H. T. Nat. Immunol. 2007; 8: PubMed Scopus Google Scholar). it has been shown that human in results in a defect in anti-fungal defense A. M. C. D. H. K. S. A. N. A. N. O. J. B. New Engl. J. Med. 2009; 361: PubMed Scopus Google Scholar). Although the molecular mechanism by which CARD9 is involved in anti-fungal responses is not fully it has been shown that cells are in zymosan-induced NF-κB activation O. A. K. M. T. C. J. 2006; PubMed Scopus Google Scholar). is a β-glucan, a of cell and a ligand for Dectin-1 (9Brown G.D. Taylor P.R. Reid D.M. Willment J.A. Williams D.L. Martinez-Pomares L. Wong S.Y. Gordon S. J. Exp. Med. 2002; 196: 407-412Crossref PubMed Scopus (797) Google Scholar). Therefore, the for fungal NF-κB activation is that fungal cell wall as β-glucan, activate and Dectin-1 activates NF-κB through a and pathway M.J. Sancho D. Slack E.C. LeibundGut-Landmann S. Reis e Sousa C. Nat. Immunol. 2006; 7: 1258-1265Crossref PubMed Scopus (421) Google Scholar, O. A. K. M. T. C. J. 2006; PubMed Scopus Google Scholar, S. O. M.J. Slack E.C. Tsoni S.V. Schweighoffer E. Tybulewicz Brown G.D. J. Reis e Sousa C. Nat. Immunol. 2007; 8: PubMed Scopus Google we demonstrated that macrophages for C. albicans-induced NF-κB activation. Our data that NF-κB activation induced by C. albicans is mainly through its hyphal which activates Dectin-2 but not Dectin-1. In NF-κB activation induced by a β-glucan from is mainly dependent on Dectin-1 but not our results that CARD9 mediates Dectin-2-induced IKK ubiquitination, but not IKK following we demonstrated that C. albicans induce NF-κB activation through pathway is induced by the unicellular form of C. albicans through Dectin-1 to activate downstream signaling whereas the other pathway is induced by the hyphal form of C. albicans through Dectin-2 to activate downstream signaling Although Syk is required for both the Dectin-1 and Dectin-2 CARD9 is mainly involved in the Dectin-2 Our data further demonstrate that Syk and CARD9 with Syk IKK phosphorylation and CARD9 IKK ubiquitination Therefore, our a for NF-κB activation in which C. albicans infection mainly induces NF-κB through a signaling of the proposed that C. albicans infection induces NF-κB through the signaling as C. albicans are from their to the hyphal the as in for cell into they are to the β-glucan in the surface of cell wall is mainly buried by other components 2006; PubMed Scopus Google Scholar), as (1Netea M.G. Brown G.D. Kullberg B.J. Gow N.A. Nat. Rev. Microbiol. 2008; 6: 67-78Crossref PubMed Scopus (686) Google Scholar). Therefore, it is that macrophages recognize the on their surface of and to activation of inflammatory signaling Our that Dectin-2 is required for Hyphae-induced NF-κB activation and are with that Dectin-2 with a Rosas M. Brown G.D. S. Wong S.Y. Gordon S. Martinez-Pomares L. Taylor P.R. 2006; 16: PubMed Scopus Google Scholar) and that C. albicans contains on its cell wall E. S. A. PubMed Scopus Google Scholar). Although our that is not to activate NF-κB not it be to is required for data that CARD9 is required for the inflammatory response induced by the hyphal form of C. albicans but not by C. albicans that the inflammatory response induced by C. albicans is not induced by β-glucan in the cell wall of C. with we found that as and induce NF-κB through a This to a that zymosan-induced NF-κB is dependent on CARD9 O. A. K. M. T. C. J. 2006; PubMed Scopus Google Scholar). In our we used both and and demonstrated that the translocation of NF-κB and IκB is not in Although we the the role of CARD9 in zymosan-induced NF-κB activation our results and by O. A. K. M. T. C. J. 2006; PubMed Scopus Google Scholar), is that used marrow-derived dendritic cells, whereas we used marrow-derived However, in our we a of NF-κB activation in and CARD9 dendritic cells M.J. Rosas M. Schweighoffer E. O. J. Tybulewicz Brown G.D. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; PubMed Scopus Google Scholar) that Dectin-1 and Dectin-2 to in a for immunity M.J. Rosas M. Schweighoffer E. O. J. Tybulewicz Brown G.D. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; PubMed Scopus Google Scholar). data also that Syk functions downstream of both Dectin-1 and Dectin-2 but of Our data the that Syk functions downstream of both Dectin-1 and However, our results that Dectin-1 and Dectin-2 in response to different from C. In we find that inhibiting Dectin-2 expression NF-κB and The our of is to the that used Dectin-2 to the of surface whereas we used Dectin-2 to Dectin-2 During the process of our S. S. K. S. H. A. Fujikado N. T. S. Chung S.H. R. N. Adachi Y. Ohno N. K. N. Kawakami K. S. T. Akira S. Iwakura Y. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar) a that but not are to C. albicans results also show that CARD9 is with following stimulation of the which that CARD9 functions downstream of However, it remains to be determined CARD9 to Dectin-2 In addition, we find that CARD9 deficiency signal-induced IKK ubiquitination, whereas of Syk activity the signal-induced IKK that CARD9 and Syk not in a in the signaling pathway following C. albicans our data that Dectin-2 expression NF-κB activation demonstrate that Dectin-2 is an essential of the receptor for mediating C. albicans NF-κB activation, we the that other as also in mediating C. albicans NF-κB activation. to Dectin-2 is the it also a complex with other receptors to NF-κB several be from our C. albicans induces the response mainly through its hyphal form. components other β-glucan on the hyphal surface are by Dectin-2 on The stimulation of Dectin-2 by hyphae induces signaling cascades in which the regulates IKK whereas the IKK phosphorylation and ubiquitination of the IKK complex induce its kinase activity and to phosphorylation and degradation of IκBα and activation of NF-κB Together, our a molecular mechanism of fungal inflammatory response and for infection. IntroductionCandida albicans is a major opportunistic fungal pathogen that predominantly causes infection to cancer patients and immunocompromised individuals. During C. albicans infection, macrophages and dendritic cells recognize components from the fungal cell wall through their pattern recognition receptors (1Netea M.G. Brown G.D. Kullberg B.J. Gow N.A. Nat. Rev. Microbiol. 2008; 6: 67-78Crossref PubMed Scopus (686) Google Scholar, 2Robinson M.J. Sancho D. Slack E.C. LeibundGut-Landmann S. Reis e Sousa C. Nat. Immunol. 2006; 7: 1258-1265Crossref PubMed Scopus (421) Google Scholar), which triggers a series of signaling cascades leading to activation of various transcription factors including NF-κB (1Netea M.G. Brown G.D. Kullberg B.J. Gow N.A. Nat. Rev. Microbiol. 2008; 6: 67-78Crossref PubMed Scopus (686) Google Scholar). The activation of NF-κB and other transcription factors further induce the expression of various cytokines and chemokines and inflammatory responses. However, the pattern recognition receptors that recognize fungal cell wall components are not fully defined (3Willment J.A. Brown G.D. Trends Microbiol. 2008; 16: 27-32Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar).NF-κB is a family of transcription factors that control the expression of pro-inflammatory genes in immune cells (4Hayden M.S. Ghosh S. Cell. 2008; 132: 344-362Abstract Full Text Full Text PDF PubMed Scopus (3447) Google Scholar). In resting cells, the activity of NF-κB is tightly controlled by the IκB family of proteins, which bind to NF-κB dimers and keep these dimers in the cytoplasm. The canonical NF-κB activation pathway by most of NF-κB-inducing stimuli activates the IκBα kinase (IKK) 2The abbreviations used are: IKKIκBα kinaseTLRToll-like receptorLPSlipopolysaccharideERKextracellular signal-regulated kinaseBMDMbone marrow-derived macrophageshRNAsmall hairpin RNAILinterleukinEMSAelectrophoretic mobility shift assayMOImultiplicity of infection. complex. The IKK complex is controlled by signal-induced phosphorylation of IKKα and IKKβ subunits (5Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4046) Google Scholar) and signal-induced K63-linked ubiquitination of the regulatory subunit NEMO (6Chen Z.J. Nat. Cell Biol. 2005; 7: 758-765Crossref PubMed Scopus (1009) Google Scholar). The activated IKK complex in turn phosphorylates IκBα proteins on N-terminal conserved serine residues to target them for ubiquitination-dependent degradation (5Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4046) Google Scholar). This process releases NF-κB and allows its translocation into the nucleus for the activation of its target genes (4Hayden M.S. Ghosh S. Cell. 2008; 132: 344-362Abstract Full Text Full Text PDF PubMed Scopus (3447) Google Scholar). Although it has been shown that bacterial and viral infections induce IKK activation by Toll-like receptors (TLRs), the molecular mechanism by which fungal infection induces NF-κB activation is not fully defined.Dectin-1 is a glycosylated type II transmembrane receptor and is mainly expressed in myeloid cells (7Ariizumi K. Shen G.L. Shikano S. Xu S. Ritter 3rd, R. Kumamoto T. Edelbaum D. Morita A. Bergstresser P.R. Takashima A. J. Biol. Chem. 2000; 275: 20157-20167Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar). It contains a single extracellular C-type lectin-like domain and a cytoplasmic domain containing an immunoreceptor tyrosine-based activation-like motif (7Ariizumi K. Shen G.L. Shikano S. Xu S. Ritter 3rd, R. Kumamoto T. Edelbaum D. Morita A. Bergstresser P.R. Takashima A. J. Biol. Chem. 2000; 275: 20157-20167Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 8Reid D.M. Gow N.A. Brown G.D. Curr. Opin. Immunol. 2009; 21: 30-37Crossref PubMed Scopus (217) Google Scholar). The ligand for Dectin-1 is β-glucan (9Brown G.D. Taylor P.R. Reid D.M. Willment J.A. Williams D.L. Martinez-Pomares L. Wong S.Y. Gordon S. J. Exp. Med. 2002; 196: 407-412Crossref PubMed Scopus (797) Google Scholar,10Brown G.D. Herre J. Williams D.L. Willment J.A. Marshall A.S. Gordon S. J. Exp. Med. 2003; 197: 1119-1124Crossref PubMed Scopus (983) Google Scholar), a carbohydrate found in the cell wall of plant and fungi. Upon binding to β-glucan, Dectin-1 recruits and activates Syk (11Underhill D.M. Rossnagle E. Lowell C.A. Simmons R.M. Blood. 2005; 106: 2543-2550Crossref PubMed Scopus (401) Google Scholar, 12Rogers N.C. Slack E.C. Edwards A.D. Nolte M.A. Schulz O. Schweighoffer E. Williams D.L. Gordon S. Tybulewicz V.L. Brown G.D. Reis e Sousa C. Immunity. 2005; 22: 507-517Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar), an intracellular tyrosine kinase, through its immunoreceptor tyrosine-based activation-like motif, which triggers several intracellular signaling cascades leading to induction of various cytokines (10Brown G.D. Herre J. Williams D.L. Willment J.A. Marshall A.S. Gordon S. J. Exp. Med. 2003; 197: 1119-1124Crossref PubMed Scopus (983) Google Scholar, 13Gantner B.N. Simmons R.M. Canavera S.J. Akira S. Underhill D.M. J. Exp. Med. 2003; 197: 1107-1117Crossref PubMed Scopus (1309) Google Scholar, 14Gantner B.N. Simmons R.M. Underhill D.M. EMBO J. 2005; 24: 1277-1286Crossref PubMed Scopus (503) Google Scholar). In addition, it has been shown that Dectin-1 collaborates with TLRs to activate inflammatory responses following fungal infection (14Gantner B.N. Simmons R.M. Underhill D.M. EMBO J. 2005; 24: 1277-1286Crossref PubMed Scopus (503) Google Scholar). Therefore, it has been proposed that Dectin-1 functions as a pattern recognition receptor for fungal infection and mediates anti-fungus immune responses (8Reid D.M. Gow N.A. Brown G.D. Curr. Opin. Immunol. 2009; 21: 30-37Crossref PubMed Scopus (217) Google Scholar, 14Gantner B.N. Simmons R.M. Underhill D.M. EMBO J. 2005; 24: 1277-1286Crossref PubMed Scopus (503) Google Scholar, 15Brown G.D. Nat. Rev. 2006; 6: 33-43Google Scholar). Although the definite role of Dectin-1 in anti-fungus immunity remains to be fully determined (16Saijo S. Fujikado N. Furuta T. Chung S.H. Kotaki H. Seki K. Sudo K. Akira S. Adachi Y. Ohno N. Kinjo T. Nakamura K. Kawakami K. Iwakura Y. Nat. Immunol. 2007; 8: 39-46Crossref PubMed Scopus (511) Google Scholar, 17Taylor P.R. Tsoni S.V. Willment J.A. Dennehy K.M. Rosas M. Findon H. Haynes K. Steele C. Botto M. Gordon S. Brown G.D. Nat. Immunol. 2007; 8: 31-38Crossref PubMed Scopus (880) Google Scholar), the deficiency in human Dectin-1 expression results in a defect of mucosal anti-fungal defense (18Ferwerda B. Ferwerda G. Plantinga T.S. Willment J.A. van Spriel A.B. Venselaar H. Elbers C.C. Johnson M.D. Cambi A. Huysamen C. Jacobs L. Jansen T. Verheijen K. Masthoff L. Morré S.A. Vriend G. Williams D.L. Perfect J.R. Joosten L.A. Wijmenga C. van der Meer J.W. Adema G.J. Kullberg B.J. Brown G.D. Netea M.G. New Engl. J. Med. 2009; 361: 1760-1767Crossref PubMed Scopus (588) Google Scholar). In addition, it has been shown that β-glucan on the surface of C. albicans is predominantly buried beneath a monoprotein coat upon C. albicans into its hyphal form the infection 2006; PubMed Scopus Google Scholar). Therefore, the β-glucan on the cell wall of C. albicans is for the that the immunity is also induced by other components β-glucan on the surface of C. is C-type lectin-like receptor and is expressed in myeloid cells K. Shen G.L. Shikano S. Ritter 3rd, R. Edelbaum D. Morita A. Takashima A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). In to Dectin-2 not an immunoreceptor tyrosine-based activation-like motif in its cytoplasmic K. Shen G.L. Shikano S. Ritter 3rd, R. Edelbaum D. Morita A. Takashima A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Brown G.D. 2009; PubMed Scopus Google Scholar). The extracellular domain of Dectin-2 to for as and Rosas M. Brown G.D. S. Wong S.Y. Gordon S. Martinez-Pomares L. Taylor P.R. 2006; 16: PubMed Scopus Google Scholar), that these be the ligand for It has been that Dectin-2 recruits intracellular signaling leading to activation of NF-κB upon the hyphal form of C. albicans K. T. Chung J. K. Underhill D. K. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Rosas M. Schweighoffer E. O. J. Tybulewicz Brown G.D. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; PubMed Scopus Google Scholar). However, the molecular mechanism by which Dectin-2 mediates anti-fungus immunity is not fully characterized. In addition, the ligand for Dectin-2 and the signaling pathway induced by Dectin-2 to be is an adaptor protein that contains an N-terminal domain and a domain and is mainly expressed in myeloid cells J. Y. L. M.D. S. M.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Y. D. H. O. C. Nat. Immunol. 2007; 8: PubMed Scopus Google Scholar). demonstrate that CARD9 plays bacterial and fungal infection, and are to and C. albicans infection Y. Y. D. H. O. C. Nat. Immunol. 2007; 8: PubMed Scopus Google Scholar, O. A. K. M. T. C. J. 2006; PubMed Scopus Google Scholar, H. C. A. T. L. M. T. A. S. Iwakura Y. Ohno N. H. 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J. 2006; PubMed Scopus Google Scholar, S. O. M.J. Slack E.C. Tsoni S.V. Schweighoffer E. Tybulewicz Brown G.D. J. Reis e Sousa C. Nat. Immunol. 2007; 8: PubMed Scopus Google we demonstrated that macrophages for C. albicans-induced NF-κB activation. Our data that NF-κB activation induced by C. albicans is mainly through its hyphal which activates Dectin-2 but not Dectin-1. In NF-κB activation induced by a β-glucan from is mainly dependent on Dectin-1 but not our results that CARD9 mediates Dectin-2-induced IKK ubiquitination, but not IKK following stimulation.
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