CARD9 Mediates Dectin-2-induced IκBα Kinase Ubiquitination Leading to Activation of NF-κB in Response to Stimulation by the Hyphal Form of Candida albicans*

  • Liangkuan Bi
    Affiliations
    Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030

    Department of Burns, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
    Search for articles by this author
  • Sara Gojestani
    Affiliations
    Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030

    Cancer Biology Program, Graduate School of Biomedical Sciences, University of Texas, Houston, Texas 77030
    Search for articles by this author
  • Weihui Wu
    Affiliations
    Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030
    Search for articles by this author
  • Yen-Michael S. Hsu
    Affiliations
    Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030

    Immunology Program, Graduate School of Biomedical Sciences, University of Texas, Houston, Texas 77030
    Search for articles by this author
  • Jiayuan Zhu
    Affiliations
    Department of Burns, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
    Search for articles by this author
  • Kiyoshi Ariizumi
    Affiliations
    Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
    Search for articles by this author
  • Xin Lin
    Correspondence
    Recipient of the Scholar Award from the Leukemia and Lymphoma Society and the Investigator Award of Cancer Research Institute. To whom correspondence should be addressed: Dept. of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 108, Houston, TX 77030. Tel.: 713-792-8969; Fax: 713-794-3270
    Affiliations
    Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030

    Cancer Biology Program, Graduate School of Biomedical Sciences, University of Texas, Houston, Texas 77030

    Immunology Program, Graduate School of Biomedical Sciences, University of Texas, Houston, Texas 77030
    Search for articles by this author
  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grants RO1AI050848, RO1GM079451, and R01GM065899 (to X. L.). This work was also supported in part by a Graduate Student Fellowship from the China Scholarship Council (to L. B.).
    The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S8.
      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.

      REFERENCES

        • Netea M.G.
        • Brown G.D.
        • Kullberg B.J.
        • Gow N.A.
        Nat. Rev. Microbiol. 2008; 6: 67-78
        • Robinson M.J.
        • Sancho D.
        • Slack E.C.
        • LeibundGut-Landmann S.
        • Reis e Sousa C.
        Nat. Immunol. 2006; 7: 1258-1265
        • Willment J.A.
        • Brown G.D.
        Trends Microbiol. 2008; 16: 27-32
        • Hayden M.S.
        • Ghosh S.
        Cell. 2008; 132: 344-362
        • Karin M.
        • Ben-Neriah Y.
        Annu. Rev. Immunol. 2000; 18: 621-663
        • Chen Z.J.
        Nat. Cell Biol. 2005; 7: 758-765
        • Ariizumi 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: 20157-20167
        • Reid D.M.
        • Gow N.A.
        • Brown G.D.
        Curr. Opin. Immunol. 2009; 21: 30-37
        • Brown 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: 407-412
        • Brown G.D.
        • Herre J.
        • Williams D.L.
        • Willment J.A.
        • Marshall A.S.
        • Gordon S.
        J. Exp. Med. 2003; 197: 1119-1124
        • Underhill D.M.
        • Rossnagle E.
        • Lowell C.A.
        • Simmons R.M.
        Blood. 2005; 106: 2543-2550
        • Rogers 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: 507-517
        • Gantner B.N.
        • Simmons R.M.
        • Canavera S.J.
        • Akira S.
        • Underhill D.M.
        J. Exp. Med. 2003; 197: 1107-1117
        • Gantner B.N.
        • Simmons R.M.
        • Underhill D.M.
        EMBO J. 2005; 24: 1277-1286
        • Brown G.D.
        Nat. Rev. 2006; 6: 33-43
        • Saijo 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: 39-46
        • Taylor 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: 31-38
        • Ferwerda 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: 1760-1767
        • Wheeler R.T.
        • Fink G.R.
        PLoS Pathog. 2006; 2: e35
        • Ariizumi K.
        • Shen G.L.
        • Shikano S.
        • Ritter 3rd, R.
        • Zukas P.
        • Edelbaum D.
        • Morita A.
        • Takashima A.
        J. Biol. Chem. 2000; 275: 11957-11963
        • Graham L.M.
        • Brown G.D.
        Cytokine. 2009; 48: 148-155
        • McGreal E.P.
        • Rosas M.
        • Brown G.D.
        • Zamze S.
        • Wong S.Y.
        • Gordon S.
        • Martinez-Pomares L.
        • Taylor P.R.
        Glycobiology. 2006; 16: 422-430
        • Sato 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: 38854-38866
        • Robinson 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: 2037-2051
        • Bertin 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: 41082-41086
        • Hsu Y.M.
        • Zhang Y.
        • You Y.
        • Wang D.
        • Li H.
        • Duramad O.
        • Qin X.F.
        • Dong C.
        • Lin X.
        Nat. Immunol. 2007; 8: 198-205
        • Gross O.
        • Gewies A.
        • Finger K.
        • Schäfer M.
        • Sparwasser T.
        • Peschel C.
        • Förster I.
        • Ruland J.
        Nature. 2006; 442: 651-656
        • Hara 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: 619-629
        • Glocker 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: 1727-1735
        • LeibundGut-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: 630-638
        • Xue L.
        • Morris S.W.
        • Orihuela C.
        • Tuomanen E.
        • Cui X.
        • Wen R.
        • Wang D.
        Nat. Immunol. 2003; 4: 857-865
        • Kawai T.
        • Adachi O.
        • Ogawa T.
        • Takeda K.
        • Akira S.
        Immunity. 1999; 11: 115-122
        • Goodridge H.S.
        • Shimada T.
        • Wolf A.J.
        • Hsu Y.M.
        • Becker C.A.
        • Lin X.
        • Underhill D.M.
        J. Immunol. 2009; 182: 1146-1154
        • Mora-Montes H.M.
        • López-Romero E.
        • Zinker S.
        • Ponce-Noyola P.
        • Flores-Carreón A.
        Glycobiology. 2004; 14: 593-598
        • Saijo 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: 681-691