Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Language

English

Abstract

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 (InsP3R) plays a critical role in this process. However, the molecular pathways linking the InsP3R-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 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.

Conclusions

Our data have revealed an important role of the InsP3R-SEC5 interaction in innate immune responses against C. albicans.

Keywords

Inositol 1, 4, 5-trisphosphate receptors (InsP3R), Exocyst complex component 2 (SEC5), Tank-binding kinase 1 (TBK1), Antifungal innate immune response

Publication Date

4-2018

Source Publication Title

BMC Biology

Volume

16

Start Page

46

Publisher

BioMed Central

Peer Reviewed

1

Copyright

© Yang et al. 2018

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Funder

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.

DOI

10.1186/s12915-018-0507-6

Link to Publisher's Edition

http://dx.doi.org/10.1186/s12915-018-0507-6

ISSN (electronic)

17417007

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