An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

Onji, Masahiro; Kanno, Ariyo; Saitoh, Shin-Ichiroh; Fukui, Ryutaro; Motoi, Yuji; Shibata, Takuma; Matsumoto, Fumi; Lamichhane, Aayam; Sato, Shintaro; Kiyono, Hiroshi; Yamamoto, Kazuhide; Miyake, Kensuke

doi:10.1038/ncomms2949

Cited by 77 publications

(107 citation statements)

References 27 publications

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“…1b). Unc93B1, a multiple transmembrane protein, associates with TLR7 or 9 and transports them from the ER to endolysosomes 13,15,21 . Our recent study shows that TLR9 is expressed on the surface of splenic DCs in a Unc93B1-dependent manner 21 .…”

Section: Resultsmentioning

confidence: 99%

“…Unc93B1, a multiple transmembrane protein, associates with TLR7 or 9 and transports them from the ER to endolysosomes 13,15,21 . Our recent study shows that TLR9 is expressed on the surface of splenic DCs in a Unc93B1-dependent manner 21 . Cell surface TLR7 expression was also dependent on Unc93B1 because cell surface TLR7 was not detected on splenic DCs from Unc93b1 3d/3d mice, which harbour a loss-of-function mutation in the Unc93b1 gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cell surface expression of TLR9 has been recently reported 21,27 . One anti-TLR9 mAb detects TLR9 in membrane-permeabilized staining but not in cell surface staining 21 .…”

Section: Discussionmentioning

confidence: 99%

“…One anti-TLR9 mAb detects TLR9 in membrane-permeabilized staining but not in cell surface staining 21 . In contrast, the other anti-TLR9 mAb is able to detect TLR9 in both membranepermeabilized and cell surface staining.…”

Section: Discussionmentioning

confidence: 99%

“…Unc93B1 is required for the trafficking of TLR7 and TLR9 to the cell surface 21 . Unc93B1 plays a role in TLR trafficking not only to endolysosomes but also to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

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Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

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Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1 D34A/D34A mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Cell surface expression of TLR9 has been recently reported 21,27 . One anti-TLR9 mAb detects TLR9 in membrane-permeabilized staining but not in cell surface staining 21 .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Unc93B1 is required for the trafficking of TLR7 and TLR9 to the cell surface 21 . Unc93B1 plays a role in TLR trafficking not only to endolysosomes but also to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

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Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

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Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system

2017

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The history of mankind has been plagued by the tug of war with viral infections. Toll-like receptors (TLRs) and other receptors of the innate immune system constitute an early defense system against invading viruses by recognizing the viral genetic material, the nucleic acids (NAs). Agonistic ligands of NA-sensing TLRs play an emerging role in the treatment of viral diseases, demonstrating a crucial role of these receptors. Recently, crystal structures have afforded new insights into TLR recognition of NAs. An aberrant activation by self-NAs, which leads to the inflammation and autoimmunity, is avoided by strict regulation of NA-TLR interaction at multiple check-points. This Review summarizes the novel structural understanding of NA-sensing by TLRs and regulatory mechanisms of these receptors.

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Endocytosis‐free DNA sensing by cell surface TLR9 in neutrophils: Rapid defense with autoimmune risks

Miyake

Onji

2013

Eur J Immunol

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TLRs sense a variety of microbial products. Cell surface TLRs, including TLR4/MD-2, TLR1/TLR2, and TLR6/TLR2, recognize microbial membrane lipids, whereas TLR3, TLR7, TLR8, and TLR9 localize to intracellular organelles and recognize microbial nucleic acids [1][2][3]. TLR9 recognizes single-stranded DNA. Selfversus-pathogen discrimination by TLR9 is primarily dependent on structural differences between self and microbial DNA such as unmethylated CpG motifs in viral DNA [4][5][6]. CpG motifs are more often found in microbial genomes than in mammalian genomes, enabling pathogen-specific DNA recognition by TLR9. However, several studies reveal that mammalian DNA also activates TLR9Correspondence: Dr. Kensuke Miyake e-mail: kmiyake@ims.u-tokyo.ac.jp [7]. Self-versus-pathogen discrimination by TLR9 is thus error prone and one way to make this process more robust is by compartmentalizing DNA sensing in endolysosomes, rather than it taking place on the cell surface. While self-derived DNA is rapidly degraded by DNase II, microbial DNA is resistant to degradation because it is encased in bacterial cell walls or viral particles. Microbial DNA, but not self-derived DNA, therefore reaches TLR9 by way of endocytosis and trafficking through endolysosomes. In autoimmune diseases such as systemic lupus erythematosus or psoriasis, self-DNA released from dead cells is complexed with autoantibodies or the cationic antimicrobial peptide LL37. These complexes are resistant to degradation, and are delivered into endosomal compartments by endocytosis, and activate TLR9, leading to DC activation and production of .To compartmentalize DNA sensing, two mechanisms are proposed. The first mechanism depends on the proteolytic cleavagewww.eji-journal.eu Eur. J. Immunol. 2013. 43: 2006 HIGHLIGHTS 2007 of the TLR9 ectodomain in endolysosomes [11,12], on which DNA sensing is thought to depend. The ectodomain of TLR9 is cleaved by asparagine endopeptidase and cathepsins in endolysosomes [13,14]. The C-terminal TLR9 fragment (TLR9C) starting at 461T or 467F [15] is essential for triggering an activation signal. Requirement for the N-terminal TLR9 fragment in DNA sensing, however, has been controversial. Although N-terminal TLR9 fragment (TLR9N) is reported to be cleaved off and not required for DNA sensing [11,12], newly established monoclonal antibodies (mAbs) to mouse endogenous TLR9 have revealed that the TLR9N remains associated with TLR9C in DCs [15]. Furthermore, this study [15] showed that TLR9C alone fails to respond to DNA, and that TLR9N coexpression is required for DNA sensing, thus demonstrating DNA sensing by both TLR9N + TLR9C. The second mechanism compartmentalizing DNA sensing is based on TLR9 transportation. Trafficking of TLR9 out of the ER is dependent on a TLR-specific chaperone, protein associated with TLR4 A (PRAT4A), and Unc93B1, a multiple transmembrane protein [16][17][18]. Without Unc93B1, nucleic acid-sensing TLRs fail to respond to nucleic acid, because all the nucleic acid-sensing TLRs remain uncleaved in the ER [16,...

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An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

Cited by 77 publications

References 27 publications

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system

Endocytosis‐free DNA sensing by cell surface TLR9 in neutrophils: Rapid defense with autoimmune risks

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