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

Tae Whan Kim, Seunghee Hong, Amjad H. Talukder, Virginia Pascual, Yong Jun Liu

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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. Toll-like receptor 9 (TLR9) senses microbial DNA in the endosomes of plasmacytoid dendritic cells (pDCs). Our biochemical approaches indicate that heterodimerization of GCA and TLR9 is important for TLR9-mediated downstream signaling and might serve to fine tune processes against viral infection.

Original languageEnglish
Pages (from-to)712-724
Number of pages13
JournalEuropean Journal of Immunology
Volume46
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

Bibliographical note

Funding Information:
This work was supported by a grant from the National Institutes of Health awarded to Y.J.L. (R01AI097348- 03). GEN2.2 cells were obtained through a Material Transfer agreement with Dr. Joel Plumas and Lawrence Chaperot from the Université Joseph Fourier, and INSERM U823, France. We also acknowledge Harrod Carson for editing the manuscript.

Funding Information:
This work was supported by a grant from the National Institutes of Health awarded to Y.J.L. (R01AI097348- 03). GEN2.2 cells were obtained through a Material Transfer agreement with Dr. Joel Plumas and Lawrence Chaperot from the Universit? Joseph Fourier, and INSERM U823, France. We also acknowledge Harrod Carson for editing the manuscript.

Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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