InsP 3 R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca 2+ eleva
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RESEARCH ARTICLE
Open Access
InsP3R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca2+ elevation and TBK1 activity Long Yang1,4†, Wenwen Gu 2†, King-Ho Cheung3, Lan Yan1, Benjamin Chun-Kit Tong3, Yuanying Jiang1,5* and Jun Yang2*
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
Background Candida albicans (C. albicans) is the most common type of infectious fungus and is usually considered to be harmless in healthy individuals. However, systemic fungal infection by C. albicans may be life-threatening in immunocompromised patients who have undergone surgery, chemotherapy, or organ or bone marrow transplantation [1, 2]. The body defends against systemic C. * Correspondence: [email protected]; [email protected] † Equal contributors 1 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China 2 NHFPC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, 2140 Xie Tu Road, Shanghai 200032, China Full list of author information is available at the end of the article
albicans infection by recruiting innate immune cells, especially macrophages and neutrophils. Early recognition of C. albicans invasion by immune cells is mediated by opsonic receptors, such as the Fcγ receptor, and dedicated pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and C-type lectins [3]. PRRs recognize microbe-specific pathogen-associated molecular pa
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