Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9.

TitleGrancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9.
Publication TypeJournal Article
Year of Publication2016
AuthorsKim TWhan, Hong S, Talukder AH, Pascual V, Liu Y-J
JournalEur J Immunol
Date Published2016 Mar
KeywordsCalcium-Binding Proteins, Cytokines, Dendritic Cells, Gene Knockdown Techniques, Humans, Interferon Regulatory Factor-7, Interferon Type I, Mitogen-Activated Protein Kinases, NF-kappa B, RNA, Small Interfering, Signal Transduction, Toll-Like Receptor 9, Two-Hybrid System Techniques

Toll-like receptors (TLRs) are playing important roles in stimulating the innate immune response and intensifying adaptive immune response against invading pathogens. Appropriate regulation of TLR activation is important to maintain a balance between preventing tumor activation and inhibiting autoimmunity. Toll-like receptor 9 (TLR9) senses microbial DNA in the endosomes of plasmacytoid dendritic cells and triggers myeloid differentiation primary response gene 88 (MyD88) dependent nuclear factor kappa B (NF-κB) pathways and type I interferon (IFN) responses. However, mechanisms of how TLR9 signals are mediated and which molecules are involved in controlling TLR9 functions remain poorly understood. Here, we report that penta EF-hand protein grancalcin (GCA) interacts and binds with TLR9 in a yeast two-hybrid system and an overexpression system. Using siRNA-mediated knockdown experiments, we also revealed that GCA positively regulates type I IFN production, cytokine/chemokine production through nuclear localization of interferon regulatory factor 7 (IRF7), NF-κB activation, and mitogen-activated protein kinase (MAPK) activation in plasmacytoid dendritic cells. Our results indicate that heterodimerization of GCA and TLR9 is important for TLR9-mediated downstream signaling and might serve to fine tune processes against viral infection.

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Alternate JournalEur. J. Immunol.
PubMed ID26648480
Grant ListR01AI097348-03 / AI / NIAID NIH HHS / United States

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