Granulin is a soluble cofactor for toll-like receptor 9 signaling

Immunity. 2011 Apr 22;34(4):505-13. doi: 10.1016/j.immuni.2011.01.018. Epub 2011 Apr 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / immunology*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligodeoxyribonucleotides / immunology
  • Progranulins
  • Protein Binding
  • Signal Transduction*
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / immunology*
  • Toll-Like Receptor 9 / metabolism


  • CPG-oligonucleotide
  • Intercellular Signaling Peptides and Proteins
  • Oligodeoxyribonucleotides
  • Progranulins
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9