Granulin is a soluble cofactor for toll-like receptor 9 signaling |
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Authors: | Park Boyoun Buti Ludovico Lee Sungwook Matsuwaki Takashi Spooner Eric Brinkmann Melanie M Nishihara Masugi Ploegh Hidde L |
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Affiliation: | Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea. bypark@yonsei.ac.kr |
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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. |
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