CARD9 mediates dectin-2-induced IkappaBalpha kinase ubiquitination leading to activation of NF-kappaB in response to stimulation by the hyphal form of Candida albicans.
The scaffold protein CARD9 plays an essential role in anti-fungus immunity and is implicated in mediating Dectin-1/Syk-induced NF-kappaB activation in response to Candida albicans infection. However, the molecular mechanism by which CARD9 mediates C. albicans-induced NF-kappaB activation is not fully characterized. Here we demonstrate that CARD9 is involved in mediating NF-kappaB 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-kappaB, whereas inhibiting Dectin-1 mainly suppressed zymosan-induced NF-kappaB, indicating that Hyphae-induced NF-kappaB 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-kappaB 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-kappaB activation, they regulate different signaling events in which CARD9 mediates IkappaBalpha kinase ubiquitination, whereas Syk regulates IkappaBalpha kinase phosphorylation. Together, our data demonstrated that CARD9 is selectively involved in Dectin-2-induced NF-kappaB activation in response to C. albicans hyphae challenging.
Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Liangkuan
L
Bi
Sara
S
Gojestani
Weihui
W
Wu
Yen-Michael S
YM
Hsu
Jiayuan
J
Zhu
Kiyoshi
K
Ariizumi
Xin
X
Lin
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D002176:Candida albicans / Q000276:immunology*; D025301:Hyphae / Q000276:immunology*; D051550:I-kappa B Kinase / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D016328:NF-kappa B; C445340:dectin-2, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051550:I-kappa B Kinase