Spatiotemporal Regulation of Heat Shock Protein 90-Chaperoned Self-DNA and CpG-Oligodeoxynucleotide for Type I IFN Induction via Targeting to Static Early Endosome

Okuya, Koichi; Tamura, Yasuaki; Saito, Keita; Kutomi, Goro; Torigoe, Toshihiko; Hirata, Koichi; Sato, Noriyuki

doi:10.4049/jimmunol.1000490

Cited by 36 publications

(36 citation statements)

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“…However, a breakdown of innate tolerance to self-nucleic acids occurs when tissue injury or necrosis causes the release of some endogenous molecules, including antimicrobial peptides such as LL37 and nuclear protein high-mobility group box 1 protein, which help to promote stabilization and delivery of associated innate ligands including nucleic acids into early endosomes. We have recently demonstrated that human extracellular Hsp90 complexed with CpG-A or self-DNA stimulates production of a large amount of IFN-α from pDCs via endosomal targeting [19]. In this study, we showed that extracellular Hsp90 found in SLE sera bound to self-DNA and is thus capable of stimulating IFN-α production when pulsed onto pDCs.…”

Section: Discussionmentioning

confidence: 64%

“…Self-derived nucleic acids, however, may reach endolysosomes in an inflammatory or autoimmune situation, where a variety of nucleic acid-binding proteins such as autoantibodies, anti-microbial peptide LL-37 [17], and a nuclear protein, high-mobility group box 1 protein [18], are complexed with host nucleic acids. We have recently demonstrated that host DNA complexed with Hsp90 stimulated TLR9 signaling, leading to robust IFN-α production [19]. These complexes are resistant to degradation, reach the endolysosomes, and stimulate TLR7 and TLR9.…”

Section: Introductionmentioning

confidence: 99%

“…Otsu, Shiga, Japan). The generation of Hsp90-DNA complex was described elsewhere [19]. Briefly, purified DNA (20 μg) and Hsp90 (20 μg) were mixed and incubated for 30 min at 37°C.…”

Section: Detection Of Hsp90-bound Self-dna and Anti-dna Abmentioning

confidence: 99%

“…Of interest, extracellular self-Hsp90 found in SLE sera could stimulate IFN-α production by pDCs, and we found that extracellular self-Hsp90 associates with self-DNA or an anti-DNA antibody-self-DNA complex. This Hsp90-self-DNA complex or Hsp90-anti-DNA autoantibody-self-DNA complex might be efficiently endocytosed and targeted to early endosomes via the action of Hsp90, leading to the robust IFN-α production observed in SLE sera [19]. Moreover, we showed that immunodepletion of extracellular Hsp90 from SLE serum decreased IFN-α production, indicating that Hsp90 absorption using a column during hemodialysis might reduce disease activity, and induce remission and prevent end-organ damage.…”

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Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

et al. 2015

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Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease, and disease activity is associated with serum IFN-α level. Plasmacytoid dendritic cells (pDCs) sense microbial as well as self-nucleic acids by TLRs 7 and 9 and produce a large amount of IFN-α. Here, we show that heat shock protein 90 (Hsp90) associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Inhibition of Hsp90 by various approaches including the use of Hsp90 inhibitor, a geldanamycin derivative, suppressed the Hsp90 association with TLR7/9, which resulted in inhibition of IFN-α production, leading to improvement of SLE symptoms in mice. Notably, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Furthermore, we demonstrated that serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Our data demonstrate that Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases.Keywords: Hsp90 r IFN-α r Plasmacytoid DC r SLE r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is characterized by the generation of autoantibodies specific for native double-stranded (ds) Correspondence: Prof. Yasuaki Tamura e-mail: ytamura3566@gmail.com DNA and nucleic acid/protein complexes [1]. A growing body of evidence suggests that IFN-α promotes lupus [2], since many patients have elevated serum IFN-α levels [3,4] and PBMCs from patients exhibit an IFN-α-induced gene expression signature that correlates with disease severity [5,6]. Recent findings in both human and mouse models suggest that TLR7 and TLR9 may play central roles in maintenance and progression of the disease by C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2028-2041 Innate immunity 2029 promoting elevation of IFN-α levels from plasmacytoid dendritic cells (pDCs) [7][8][9] and by activating B cells to produce autoantibodies [10,11]. pDCs sense microbial nucleic acids by TLR7 and TLR9 and produce a large amount of IFN-α. pDCs specifically express TLR7 and TLR9 within endolysosmes, and TLR7 and TLR9 sense single-stranded RNA and unmethylated CpG-rich DNA [12][13][14][15]. Importantly, microbial nucleic acids share a basic structure with host-derived nucleic acids. Indeed, TLR9 is able to respond to mammalian DNA if expressed on the cell surface [16]. TLR7 also responds to host-derived single-stranded RNA [7]. Therefore, nucleic acid-sensing TLR7/9 has to be tightly controlled to avoid autoimmune reaction. Nucleic acid sensing within endolysosomes is thought to be a safety mechanism for self-nucleic acid, because self-nucleic acids are rapidly degraded by DNase and RNase before reaching endolysosomes. Self-derived nuc...

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

“…Otsu, Shiga, Japan). The generation of Hsp90-DNA complex was described elsewhere [19]. Briefly, purified DNA (20 μg) and Hsp90 (20 μg) were mixed and incubated for 30 min at 37°C.…”

Section: Detection Of Hsp90-bound Self-dna and Anti-dna Abmentioning

confidence: 99%

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confidence: 99%

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Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

et al. 2015

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“…There is mounting evidence that both subcellular localization and endosomal pH can influence the ability of endosomal TLRs to signal. For example, the TLR9 response to exogenous CpG DNA is dependent on specific endosomal localization and acidification (Guiducci et al , 2006; Yao et al , 2009; Okuya et al , 2010; Hazeki et al , 2013; Duhamel et al , 2016). Sasai et al (2010) showed TLR9 signaling leading to activation of type I IFN but not pro‐inflammatory cytokine genes require TLR9 trafficking from endosomes to a specialized lysosome‐related organelle dependent on AP‐3.…”

Section: Discussionmentioning

confidence: 99%

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

et al. 2017

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HIV‐1 traffics through dendritic cells (DCs) en route to establishing a productive infection in T lymphocytes but fails to induce an innate immune response. Within DC endosomes, HIV‐1 somehow evades detection by the pattern‐recognition receptor (PRR) Toll‐like receptor 8 (TLR8). Using a phosphoproteomic approach, we identified a robust and diverse signaling cascade triggered by HIV‐1 upon entry into human DCs. A secondary siRNA screen of the identified signaling factors revealed several new mediators of HIV‐1 trans‐infection of CD4+ T cells in DCs, including the dynein motor protein Snapin. Inhibition of Snapin enhanced localization of HIV‐1 with TLR8+ early endosomes, triggered a pro‐inflammatory response, and inhibited trans‐infection of CD4+ T cells. Snapin inhibited TLR8 signaling in the absence of HIV‐1 and is a general regulator of endosomal maturation. Thus, we identify a new mechanism of innate immune sensing by TLR8 in DCs, which is exploited by HIV‐1 to promote transmission.

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Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity

Perl

2016

Arthritis & Rheumatology

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Spatiotemporal Regulation of Heat Shock Protein 90-Chaperoned Self-DNA and CpG-Oligodeoxynucleotide for Type I IFN Induction via Targeting to Static Early Endosome

Abstract: Material

Cited by 36 publications

References 45 publications

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity

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