title: Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9.
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.
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX, USA.
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX, USA.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Amjad H
authors.initials: AH
authors.lastname: Talukder
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX, USA.|MedImmune, Inc, Gaithersburg, MD, USA.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; C503121:GCA protein, human; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D020928:Mitogen-Activated Protein Kinases
keywords: Grancalcin; IRF7; Plasmacytoid dendritic cells; TLR9 signaling; Type I interferon