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 Ca(2+) levels via the inositol 1,4,5-trisphosphate receptor (InsP(3)R) plays a critical role in this process. However, the molecular pathways linking the InsP(3)R-mediated increase in Ca(2+) 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 InsP(3)R channel activity by binding to its C-terminal α-helix (H1), increasing cytosolic Ca(2+) concentrations ([Ca(2+)](c)). Immunofluorescence reveals enriched InsP(3)R-SEC5 complex formation on phagosomes, while disruption of the InsP(3)R-SEC5 interaction by recombinant H1 peptides attenuates the InsP(3)R-mediated Ca(2+) elevation, leading to impaired phagocytosis. Furthermore, we show that C. albicans infection promotes the recruitment of Tank-binding kinase 1 (TBK1) by the InsP(3)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 InsP(3)R-SEC5 interaction may regulate antifungal innate immune responses not only by elevating cytoplasmic Ca(2+) but also by activating the TBK1-IRF-3 pathway. CONCLUSIONS: Our data have revealed an important role of the InsP(3)R-SEC5 interaction in innate immune responses against C. albicans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12915-018-0507-6) contains supplementary material, which is available to authorized users.