Candida albicans beta-glucan exposure is controlled by the fungal CEK1-mediated mitogen-activated protein kinase pathway that modulates immune responses triggered through dectin-1.
Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as beta-glucan seems to be a mechanism that fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall beta-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IkappaB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in beta-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.
Galán-Díez
Marta
M
Unidad de Biología Molecular, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
Arana
David M
DM
Serrano-Gómez
Diego
D
Kremer
Leonor
L
Casasnovas
José M
JM
Ortega
Mara
M
Cuesta-Domínguez
Alvaro
A
Corbí
Angel L
AL
Pla
Jesús
J
Fernández-Ruiz
Elena
E
D002176:Candida albicans / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D055786:Gene Knockout Techniques; D006801:Humans; D037181:Lectins, C-Type; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D050296:Microbial Viability; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D047071:beta-Glucans / Q000276:immunology / Q000378:metabolism*; D000099181:Dectin-1
D016207:Cytokines; D005656:Fungal Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D047071:beta-Glucans; D000099181:Dectin-1; C077339:CEK1 protein, Candida albicans