期刊
IMMUNITY
卷 34, 期 4, 页码 505-513出版社
CELL PRESS
DOI: 10.1016/j.immuni.2011.01.018
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资金
- Ministry of Education, Science and Technology [2010-0009203]
- Korean Government [KRF-2007-357-000086]
- Yonsei University
- Landon Clay fellowship
- NIH and Novartis
- Novartis
- Charles A. King Trust, Bank of America
- National Research Foundation of Korea [2010-0009203, 2007-357-C00086] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Grants-in-Aid for Scientific Research [23228004, 20248030] Funding Source: KAKEN
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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