School of Chinese Medicine
Candida albicans (C. albicans) invasion triggers antifungal innate immunity, and the elevation of cytoplasmic Ca2+ levels via the inositol 1,4,5-trisphosphate receptor (InsP3R) plays a critical role in this process. However, the molecular pathways linking the InsP3R-mediated increase in Ca2+ and immune responses remain elusive.
In the present study, we find that during C. albicans phagocytosis in macrophages, exocyst complex component 2 (SEC5) promotes InsP3R channel activity by binding to its C-terminal α-helix (H1), increasing cytosolic Ca2+ concentrations ([Ca2+]c). Immunofluorescence reveals enriched InsP3R-SEC5 complex formation on phagosomes, while disruption of the InsP3R-SEC5 interaction by recombinant H1 peptides attenuates the InsP3R-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 InsP3R-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 InsP3R-SEC5 interaction may regulate antifungal innate immune responses not only by elevating cytoplasmic Ca2+ but also by activating the TBK1-IRF-3 pathway.
Our data have revealed an important role of the InsP3R-SEC5 interaction in innate immune responses against C. albicans.
Inositol 1, 4, 5-trisphosphate receptors (InsP3R), Exocyst complex component 2 (SEC5), Tank-binding kinase 1 (TBK1), Antifungal innate immune response
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© Yang et al. 2018
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This work is licensed under a Creative Commons Attribution 4.0 License.
This work was supported by the General Research Fund of Hong Kong 764113 & 17104514 to KHC, the Shanghai Institute of Planned Parenthood Research, Pandeng Planning Grant PD2012–4 to JY, and by the National Basic Research Program of China 2013CB531602 to YYJ.
Link to Publisher's Edition
Yang, Long, Wenwen Gu, King-Ho Cheung, Lan Yan, Benjamin Chun-Kit Tong, Yuanying Jiang, and Jun Yang. "InsP3R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca2+ elevation and TBK1 activity." BMC Biology 16 (2018): 46.