Granulin Is a Soluble Cofactor for Toll-like Receptor 9 Signaling

Boyoun Park, Ludovico Buti, Sungwook Lee, Takashi Matsuwaki, Eric Spooner, Melanie M. Brinkmann, Masugi Nishihara, Hidde L. Ploegh

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116 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)505-513
Number of pages9
Issue number4
Publication statusPublished - 2011 Apr 22

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Park, B., Buti, L., Lee, S., Matsuwaki, T., Spooner, E., Brinkmann, M. M., Nishihara, M., & Ploegh, H. L. (2011). Granulin Is a Soluble Cofactor for Toll-like Receptor 9 Signaling. Immunity, 34(4), 505-513.