InsP 3 R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca 2+ elevation and TBK1 activity.

BACKGROUND: Candida albicans (C. albicans) invasion triggers antifungal innate immunity, and the elevation of cytoplasmic Ca2+ levels via the inositol 1,4,5-trisphosphate receptor (InsP3 R) plays a critical role in this process. However, the molecular pathways linking the InsP3 R-mediated increase in Ca2+ and immune responses remain elusive.

RESULTS: In the present study, we find that during C. albicans phagocytosis in macrophages, exocyst complex component 2 (SEC5) promotes InsP3 R channel activity by binding to its C-terminal α-helix (H1), increasing cytosolic Ca2+ concentrations ([Ca2+ ]c ). Immunofluorescence reveals enriched InsP3 R-SEC5 complex formation on phagosomes, while disruption of the InsP3 R-SEC5 interaction by recombinant H1 peptides attenuates the InsP3 R-mediated Ca2+ elevation, leading to impaired phagocytosis. Furthermore, we show that C. albicans infection promotes the recruitment of Tank-binding kinase 1 (TBK1) by the InsP3 R-SEC5 interacting complex, leading to the activation of TBK1. Subsequently, activated TBK1 phosphorylates interferon regulatory factor 3 (IRF-3) and mediates type I interferon responses, suggesting that the InsP3 R-SEC5 interaction may regulate antifungal innate immune responses not only by elevating cytoplasmic Ca2+ but also by activating the TBK1-IRF-3 pathway.

CONCLUSIONS: Our data have revealed an important role of the InsP3 R-SEC5 interaction in innate immune responses against C. albicans.