TY - JOUR
T1 - InsP3R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca2+ elevation and TBK1 activity
AU - Yang, Long
AU - Gu, Wenwen
AU - Cheung, King Ho
AU - Yan, Lan
AU - Tong, Benjamin Chun Kit
AU - Jiang, Yuanying
AU - Yang, Jun
N1 - Funding information:
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.
Publisher copyright:
© Yang et al. 2018
PY - 2018/4/27
Y1 - 2018/4/27
N2 - 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.
AB - 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.
KW - Antifungal innate immune response
KW - Exocyst complex component 2 (SEC5)
KW - Inositol 1,4,5-trisphosphate receptors (InsP3R)
KW - Tank-binding kinase 1 (TBK1)
UR - https://doi.org/10.1186/s12915-018-0507-6
UR - http://www.scopus.com/inward/record.url?scp=85046081214&partnerID=8YFLogxK
U2 - 10.1186/s12915-018-0507-6
DO - 10.1186/s12915-018-0507-6
M3 - Journal article
C2 - 29703257
AN - SCOPUS:85046081214
SN - 1741-7007
VL - 16
JO - BMC Biology
JF - BMC Biology
M1 - 46
ER -