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Granulin Is a Soluble Cofactor for Toll-like Receptor 9 Signaling
Park, Boyoun,Buti, Ludovico,Lee, Sungwook,Matsuwaki, Takashi,Spooner, Eric,Brinkmann, Melanie ,M.,Nishihara, Masugi,Ploegh, Hidde ,L. Elsevier 2011 Immunity Vol.34 No.4
<P><B>Summary</B></P><P>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.</P> <P><B>Highlights</B></P><P>► Granulin binds TLR9 and CpG oligonucleotides ► Granulin is sufficient for intracellular localization of CpG-ODNs ► Granulin is a critical cofactor in enabling TLR9 signal transduction</P>
Kim, Jihee,Huh, Jiwon,Hwang, Misun,Kwon, Eun-Hye,Jung, Da-Jung,Brinkmann, Melanie M.,Jang, Myoung Ho,Ploegh, Hidde L.,Kim, You-Me The American Association of Immunologists, Inc. 2013 JOURNAL OF IMMUNOLOGY Vol.190 No.10
<P>TLRs are divided into two groups based on their subcellular localization patterns. TLR1, 2, 4, 5, and 6 are expressed on the cell surface, whereas the nucleotide-sensing TLRs, such as TLR3, 7, 8, and 9 stay mainly inside cells. The polytopic membrane protein UNC93B1 physically interacts with the nucleotide-sensing TLRs and delivers them from the endoplasmic reticulum to endolysosomes, where the TLRs recognize their ligands and initiate signaling. In cells with nonfunctional UNC93B1, the nucleic acid–sensing TLRs fail to exit the endoplasmic reticulum and consequently do not signal. However, the detailed molecular mechanisms that underlie the UNC93B1-mediated TLR trafficking remain to be clarified. All nucleotide-sensing TLRs contain acidic amino acid residues in the juxtamembrane region between the leucine-rich repeat domain and the transmembrane segment. We show that the D812 and E813 residues of TLR9 and the D699 and E704 residues of TLR3 help to determine the interaction of these TLRs with UNC93B1. Mutation of the acidic residues in TLR3 and TLR9 prevents UNC93B1 binding, as well as impairs TLR trafficking and renders the mutant receptors incapable of transmitting signals. Therefore, the acidic residues in the juxtamembrane region of the nucleotide-sensing TLRs have important functional roles.</P>