title: Granulin is a soluble cofactor for toll-like receptor 9 signaling.
abstract: Toll-like receptor (TLR) signaling plays a critical role in innate and adaptive immune responses and must be tightly controlled. TLR4 uses LPS binding protein, MD-2, and CD14 as accessories to respond to LPS. We therefore investigated the presence of an analagous soluble cofactor that might assist in the recruitment of CpG oligonucleotides (CpG-ODNs) to TLR9. We report the identification of granulin as an essential secreted cofactor that potentiates TLR9-driven responses to CpG-ODNs. Granulin, an unusual cysteine-rich protein, bound to CpG-ODNs and interacted with TLR9. Macrophages from granulin-deficient mice showed not only impaired delivery of CpG-ODNs to endolysosomal compartments, but also decreased interaction of TLR9 with CpG-ODNs. As a consequence, granulin-deficient macrophages showed reduced responses to stimulation with CpG-ODNs, a trait corrected by provision of exogenous granulin. Thus, we propose that granulin contributes to innate immunity as a critical soluble cofactor for TLR9 signaling.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea. bypark@yonsei.ac.kr
authors.forename: Boyoun
authors.initials: B
authors.lastname: Park
authors.forename: Ludovico
authors.initials: L
authors.lastname: Buti
authors.forename: Sungwook
authors.initials: S
authors.lastname: Lee
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuwaki
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Brinkmann
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D000077153:Progranulins; D011485:Protein Binding; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D036341:Intercellular Signaling Peptides and Proteins; D009838:Oligodeoxyribonucleotides; D000077153:Progranulins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9