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Published on: July 26, 2017
Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9
Tae Whan Kim1, Seunghee Hong1, Amjad H Talukder2
1Baylor Institute for Immunology Research, Dallas, TX, USA.
Abstract:
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.
Insights
Grancalcin (GCA) binds Toll-like receptor 9 (TLR9), enhancing immune responses. This interaction positively regulates type I interferon and cytokine production in dendritic cells, crucial for fighting viral infections.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Toll-like receptors (TLRs) are crucial for innate and adaptive immunity.
- Toll-like receptor 9 (TLR9) recognizes microbial DNA, initiating immune signaling pathways.
- Understanding TLR9 regulation is vital for balancing anti-tumor immunity and preventing autoimmunity.
Purpose of the Study:
- To identify novel molecules involved in Toll-like receptor 9 (TLR9) signaling.
- To elucidate the regulatory role of grancalcin (GCA) in TLR9-mediated immune responses.
- To investigate the impact of GCA on type I interferon and cytokine production.
Main Methods:
- Yeast two-hybrid system and overexpression systems to identify protein interactions.
- siRNA-mediated knockdown to assess gene function.
- Analysis of downstream signaling pathways including IRF7 nuclear localization, NF-κB, and MAPK activation in plasmacytoid dendritic cells.
Main Results:
- Grancalcin (GCA) was identified to interact and bind with Toll-like receptor 9 (TLR9).
- GCA positively regulates type I interferon production and cytokine/chemokine release.
- GCA promotes nuclear localization of IRF7, NF-κB activation, and MAPK activation in plasmacytoid dendritic cells.
Conclusions:
- Grancalcin (GCA) is a positive regulator of TLR9 signaling pathways.
- The heterodimerization of GCA and TLR9 is essential for downstream signaling.
- GCA plays a significant role in fine-tuning immune responses against viral infections.
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