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• W1969668872 abstract "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 transforming C. albicans into its hyphal form under the infection condition (19Wheeler R.T. Fink G.R. PLoS Pathog. 2006; 2: e35Crossref PubMed Scopus (278) Google Scholar). Therefore, the β-glucan moiety on the cell wall of C. albicans is invisible for the host, suggesting that the host innate immunity is also induced by other components rather than β-glucan on the surface of C. albicans.Dectin-2 is another C-type lectin-like receptor and is expressed in myeloid cells (20Ariizumi K. Shen G.L. Shikano S. Ritter 3rd, R. Zukas P. Edelbaum D. Morita A. Takashima A. J. Biol. Chem. 2000; 275: 11957-11963Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). In contrast to Dectin-1, Dectin-2 does not contain an immunoreceptor tyrosine-based activation-like motif in its cytoplasmic tail (20Ariizumi K. Shen G.L. Shikano S. Ritter 3rd, R. Zukas P. Edelbaum D. Morita A. Takashima A. J. Biol. Chem. 2000; 275: 11957-11963Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 21Graham L.M. Brown G.D. Cytokine. 2009; 48: 148-155Crossref PubMed Scopus (91) Google Scholar). The extracellular carbohydrate-recognition domain of Dectin-2 appears to have specificity for high mannose such as Man9GlcNAc2 and Man8GlcNAc2 (22McGreal E.P. Rosas M. Brown G.D. Zamze S. Wong S.Y. Gordon S. Martinez-Pomares L. Taylor P.R. Glycobiology. 2006; 16: 422-430Crossref PubMed Scopus (275) Google Scholar), suggesting that these molecules may be the ligand for Dectin-2. It has been suggested that Dectin-2 recruits Fcγ triggering intracellular signaling cascades, leading to activation of NF-κB upon encountering the hyphal form of C. albicans (23Sato K. Yang X.L. Yudate T. Chung J.S. Wu J. Luby-Phelps K. Kimberly R.P. Underhill D. Cruz Jr., P.D. Ariizumi K. J. Biol. Chem. 2006; 281: 38854-38866Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 24Robinson M.J. Osorio F. Rosas M. Freitas R.P. Schweighoffer E. Gross O. Verbeek J.S. Ruland J. Tybulewicz V. Brown G.D. Moita L.F. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; 206: 2037-2051Crossref PubMed Scopus (351) Google Scholar). However, the molecular mechanism by which Dectin-2 mediates anti-fungus immunity is not fully characterized. In addition, the nature ligand for Dectin-2 and the signaling pathway induced by Dectin-2 remain to be determined.CARD9 is an adaptor protein that contains an N-terminal caspase recruitment domain and a C-terminal coiled-coil domain and is mainly expressed in myeloid cells (25Bertin J. Guo Y. Wang L. Srinivasula S.M. Jacobson M.D. Poyet J.L. Merriam S. Du M.Q. Dyer M.J. Robison K.E. DiStefano P.S. Alnemri E.S. J. Biol. Chem. 2000; 275: 41082-41086Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 26Hsu Y.M. Zhang Y. You Y. Wang D. Li H. Duramad O. Qin X.F. Dong C. Lin X. Nat. Immunol. 2007; 8: 198-205Crossref PubMed Scopus (331) Google Scholar). Recent studies demonstrate that CARD9 plays important roles against bacterial and fungal infection, and Card9-deficient mice are more susceptible to Listeria monocytogenes and C. albicans infection (26Hsu Y.M. Zhang Y. You Y. Wang D. Li H. Duramad O. Qin X.F. Dong C. Lin X. Nat. Immunol. 2007; 8: 198-205Crossref PubMed Scopus (331) Google Scholar, 27Gross O. Gewies A. Finger K. Schäfer M. Sparwasser T. Peschel C. Förster I. Ruland J. Nature. 2006; 442: 651-656Crossref PubMed Scopus (663) Google Scholar, 28Hara H. Ishihara C. Takeuchi A. Imanishi T. Xue L. Morris S.W. Inui M. Takai T. Shibuya A. Saijo S. Iwakura Y. Ohno N. Koseki H. Yoshida H. Penninger J.M. Saito T. Nat. Immunol. 2007; 8: 619-629Crossref PubMed Scopus (260) Google Scholar). More recently, it has been shown that human mutation in Card9 gene results in a defect in anti-fungal defense (29Glocker E.O. Hennigs A. Nabavi M. Schäffer A.A. Woellner C. Salzer U. Pfeifer D. Veelken H. Warnatz K. Tahami F. Jamal S. Manguiat A. Rezaei N. Amirzargar A.A. Plebani A. Hannesschläger N. Gross O. Ruland J. Grimbacher B. New Engl. J. Med. 2009; 361: 1727-1735Crossref PubMed Scopus (619) Google Scholar). Although the molecular mechanism by which CARD9 is involved in anti-fungal responses is not fully characterized, it has been shown that CARD9-deficient cells are defective in zymosan-induced NF-κB activation (27Gross O. Gewies A. Finger K. Schäfer M. Sparwasser T. Peschel C. Förster I. Ruland J. Nature. 2006; 442: 651-656Crossref PubMed Scopus (663) Google Scholar). Zymosan is a β-glucan, a component of yeast cell wall, 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 current model for fungal infection-induced NF-κB activation is that fungal cell wall components, such as β-glucan, activate Dectin-1, and then Dectin-1 activates NF-κB through a Syk- and CARD9-dependent pathway (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, 27Gross O. Gewies A. Finger K. Schäfer M. Sparwasser T. Peschel C. Förster I. Ruland J. Nature. 2006; 442: 651-656Crossref PubMed Scopus (663) Google Scholar, 30LeibundGut-Landmann S. Gross O. Robinson M.J. Osorio F. Slack E.C. Tsoni S.V. Schweighoffer E. Tybulewicz V. Brown G.D. Ruland J. Reis e Sousa C. Nat. Immunol. 2007; 8: 630-638Crossref PubMed Scopus (922) Google Scholar).In this study, we demonstrated that CARD9-deficient macrophages were defective for C. albicans-induced NF-κB activation. Our data indicate that NF-κB activation induced by live C. albicans is mainly through its hyphal form, which activates Dectin-2 but not Dectin-1. In contrast, NF-κB activation induced by zymosan, a β-glucan from yeast, is mainly dependent on Dectin-1 but not Dectin-2. Furthermore, our results indicate that CARD9 mediates Dectin-2-induced IKK ubiquitination, but not IKK phosphorylation, following Hyphae stimulation.DISCUSSIONIn this study, we have demonstrated that C. albicans can induce NF-κB activation through two independent pathways. One pathway is induced by the yeast-like, unicellular form of C. albicans through recognizing Dectin-1 to activate downstream signaling cascades, whereas the other pathway is induced by the hyphal form of C. albicans through recognizing Dectin-2 to activate downstream signaling cascades. Although Syk is required for both the Dectin-1 and Dectin-2 pathways, CARD9 is mainly involved in the Dectin-2 pathway. Our data further demonstrate that Syk and CARD9 function independently with Syk regulating IKK phosphorylation and CARD9 regulating IKK ubiquitination (Fig. 7). Therefore, our study proposes a new model for fungi-induced NF-κB activation in which C. albicans infection mainly induces NF-κB through a Dectin-2-CARD9 signaling cascade, instead of the previously proposed model that C. albicans infection induces NF-κB through the Dectin-1-Syk-CARD9 signaling cascade.Fungi such as C. albicans are rapidly transformed from their yeast forms to the hyphal forms under the vegetative growth condition, such as in condition for mammalian cell culture or after infecting into mammalian bodies. After they are transformed to hyphae, the β-glucan in the surface of yeast cell wall is mainly buried by other components (19Wheeler R.T. Fink G.R. PLoS Pathog. 2006; 2: e35Crossref PubMed Scopus (278) Google Scholar), such as monosylated glycoproteins (Mannan) (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 likely that macrophages recognize the Mannan moiety on their surface of Hyphae and lead to activation of inflammatory signaling cascades. Our findings that Dectin-2 is required for Hyphae-induced NF-κB activation and cytokine production are consistent with previous observations that Dectin-2 recognizes Man9GlcNAc2 with a high affinity (22McGreal E.P. Rosas M. Brown G.D. Zamze S. Wong S.Y. Gordon S. Martinez-Pomares L. Taylor P.R. Glycobiology. 2006; 16: 422-430Crossref PubMed Scopus (275) Google Scholar) and that C. albicans contains Man9GlcNAc2 on its cell wall (34Mora-Montes H.M. López-Romero E. Zinker S. Ponce-Noyola P. Flores-Carreón A. Glycobiology. 2004; 14: 593-598Crossref PubMed Scopus (21) Google Scholar). Although our preliminary studies indicate that Man9GlcNAc2 is not sufficient to activate NF-κB (data not shown), it will be interesting to determine whether Man9GlcNAc2 structure is required for hyphae-mediated NF-κB.Our data showing that CARD9 is required for the inflammatory response induced by the live or hyphal form of C. albicans but not by heat-inactive C. albicans suggest that the CARD9-dependent inflammatory response induced by C. albicans is not induced by β-glucan in the cell wall of C. albicans. Consistent with this notion, we have found that β-glucans, such as zymosan and curdlan, induce NF-κB through a CARD9-independent pathway. This result appears to directly contradict a previous report that zymosan-induced NF-κB is dependent on CARD9 (27Gross O. Gewies A. Finger K. Schäfer M. Sparwasser T. Peschel C. Förster I. Ruland J. Nature. 2006; 442: 651-656Crossref PubMed Scopus (663) Google Scholar). In our studies, we have used both EMSA and immunoblotting analysis and demonstrated that the nuclear translocation of NF-κB and IκB phosphorylation/degradation is not defective in CARD9-deficient macrophages. Although we cannot explain the discrepancy regarding the role of CARD9 in zymosan-induced NF-κB activation between our results and those reported by Gross et al. (27Gross O. Gewies A. Finger K. Schäfer M. Sparwasser T. Peschel C. Förster I. Ruland J. Nature. 2006; 442: 651-656Crossref PubMed Scopus (663) Google Scholar), one possible explanation is that Gross et al. used bone marrow-derived dendritic cells, whereas we used bone marrow-derived macrophages. However, in our studies, we observed only a slight difference of NF-κB activation in wild-type and CARD9 knock-out dendritic cells (supplemental Fig. S1).Recently, Robinson et al. (24Robinson M.J. Osorio F. Rosas M. Freitas R.P. Schweighoffer E. Gross O. Verbeek J.S. Ruland J. Tybulewicz V. Brown G.D. Moita L.F. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; 206: 2037-2051Crossref PubMed Scopus (351) Google Scholar) reported that Dectin-1 and Dectin-2 appear to function in a redundant manner for anti-fungi immunity (24Robinson M.J. Osorio F. Rosas M. Freitas R.P. Schweighoffer E. Gross O. Verbeek J.S. Ruland J. Tybulewicz V. Brown G.D. Moita L.F. Taylor P.R. Reis e Sousa C. J. Exp. Med. 2009; 206: 2037-2051Crossref PubMed Scopus (351) Google Scholar). Their data also suggest that Syk functions downstream of both Dectin-1 and Dectin-2 but upstream of CARD9. Our data support the notion that Syk functions downstream of both Dectin-1 and Dectin-2. However, our results argue that Dectin-1 and Dectin-2 function independently in response to different ligands from C. albicans. In particular, we find that inhibiting Dectin-2 expression completely blocks hyphae-induced NF-κB and cytokine production. The difference between our findings versus those of Robinson et al. is likely due to the fact that Robinson et al. used Dectin-2 antibodies to trigger the endocytosis of surface Dectin-2, whereas we used Dectin-2 shRNA to block Dectin-2 expression. During the reviewing process of our manuscript, Saijo et al. (35Saijo S. Ikeda S. Yamabe K. Kakuta S. Ishigame H. Akitsu A. Fujikado N. Kusaka T. Kubo S. Chung S.H. Komatsu R. Miura N. Adachi Y. Ohno N. Shibuya K. Yamamoto N. Kawakami K. Yamasaki S. Saito T. Akira S. Iwakura Y. Immunity. 2010; 32: 681-691Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar) published a paper demonstrating that Dectin-2-deficient mice but not Dectin-1-deficient mice are highly susceptible to C. albicans infection.Our results also show that CARD9 is inducibly associated with Bcl10 following stimulation of the Dectin-2-dependent pathway, which provides direct evidence that CARD9 functions downstream of Dectin-2. However, it remains to be determined what molecule(s) link CARD9 to Dectin-2 (Fig. 7). In addition, we find that CARD9 deficiency significantly affects signal-induced IKK ubiquitination, whereas inhibition of Syk activity blocks the signal-induced IKK phosphorylation, suggesting that CARD9 and Syk may not work in a linear arrangement in the signaling pathway following C. albicans stimulation.Although our data showing that suppressing Dectin-2 expression blocks hyphae-induced NF-κB activation clearly demonstrate that Dectin-2 is an essential component of the receptor for mediating C. albicans hyphae-induced NF-κB activation, we cannot rule out the possibility that other receptors, such as TLRs, may also participate in mediating C. albicans hyphae-induced NF-κB activation. Thus, future studies will need to determine whether Dectin-2 is the only component or whether it also forms a complex with other receptors to mediate hyphae-induced NF-κB activation.In summary, several important conclusions can be drawn from our study. First, C. albicans induces the host-inflammatory response mainly through its hyphal form. Second, unknown components other than β-glucan on the hyphal surface are recognized by Dectin-2 on host cells. The stimulation of Dectin-2 by hyphae induces at least two independent signaling cascades in which the Syk-dependent cascade regulates IKK phosphorylation, whereas the CARD9-dependent cascade controls IKK ubiquitination. Thus, phosphorylation and ubiquitination of the IKK complex induce its kinase activity and leads to phosphorylation and degradation of IκBα and activation of NF-κB (Fig. 7). Together, our study reveals a more detailed molecular mechanism of fungal infection-induced inflammatory response and provides potential targets for designing therapeutic agents against fungus 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 Schola" @default.
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