Granulin Is a Soluble Cofactor for Toll-like Receptor 9 Signaling
Author(s)Park, Boyoun; Buti, Ludovico; Lee, Sungwook; Matsuwaki, Takashi; Spooner, Eric; Brinkmann, Melanie M.; Nishihara, Masugi; Ploegh, Hidde; ... Show more Show less
MetadataShow full item record
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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Park, Boyoun, Ludovico Buti, Sungwook Lee, Takashi Matsuwaki, Eric Spooner, Melanie M. Brinkmann, Masugi Nishihara, and Hidde L. Ploegh. “Granulin Is a Soluble Cofactor for Toll-Like Receptor 9 Signaling.” Immunity 34, no. 4 (April 2011): 505–513. © 2011 Elsevier Inc.
Final published version