HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses

Yanai, Hideyuki; Ban, Tomohiro; Wang, Zhichao; Choi, Myoung Kwon; Kawamura, Takeshi; Negishi, Hideo; Nakasato, Makoto; Lu, Yan; Hangai, Sho; Koshiba, Ryuji; Savitsky, David; Ronfani, Lorenza; Akira, Shizuo; Bianchi, Marco E.; Honda, Kenya; Tamura, Tomohide; Kodama, Tatsuhiko; Taniguchi, Tadatsugu

doi:10.1038/nature08512

Cited by 602 publications

(532 citation statements)

References 33 publications

(64 reference statements)

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“…35,36 In the cytoplasm, HMGBs bind immunogenic nucleotides and deliver them to the cytosolic nucleic acid sensors retinoic acid-inducible gene I, MDA5, AIM2 and DAI and to the endosome nucleic acid-sensing TLRs (TLR3, TLR7 and TLR9). 7,10 Reports have also highlighted the interactions of HMGB1 with TLR9, retinoic acid-inducible gene I and TIM-3 10,37,38 and the vital role of HMGBs in autophagy regulation, 39 mitochondrial function and morphology [40][41][42] and cell proliferation. [43][44][45] Comparatively, an understanding of HMGBs in the nucleus is limited.…”

Section: Discussionmentioning

confidence: 99%

“…In HMGB 2/2 mouse embryonic fibroblasts, the replication of vesicular stomatitis virus and vesicular stomatitis Virus 1 was increased and the expression of interferon-I was suppressed, which indicates that HMGB is critical for effective antiviral innate immune responses. 10 However, in influenza virus-infected cells, HMGB1 can promote viral growth through binding to the nucleoprotein component of influenza ribonucleoprotein. 13 Additionally, depending on the target cell and the microenvironment, HMGB1 may trigger or inhibit HIV-1 replication in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9] Various studies have also highlighted the novel feature of HMGBs that function as universal sentinels for nucleic-acid-mediated innate immune responses. 7,10 Some of these studies have shown that HMGBs promiscuously recognize immunogenic nucleic acids and transduce signals to discriminate pattern recognition receptors, such as Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors and other cytosolic receptors, to initiate the innate immune response. 7,11 By contrast, other studies have shown that HMGBs can strongly suppress innate immune responses by binding with non-immunogenic nucleotides.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Rao

Yang

et al. 2014

Cell Mol Immunol

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High-mobility group box (HMGB) proteins, a family of chromatin-associated nuclear proteins, play amazingly multifaceted roles in the immune system of mammals. Thus far, little is known about the nucleocytoplasmic distribution of HMGBs in teleosts. The present study systematically investigated the dynamic localization of all six HMGB proteins in Ctenopharyngodon idella kidney (CIK) cells. Under basal conditions, all HMGBs exclusively localized to the nucleus. Grass carp reovirus (GCRV), polyinosinic-polycytidylic (poly(I : C)) potassium salt and lipopolysaccharide (LPS) challenge evoked the nuclear export of HMGBs to various degrees: GCRV challenge induced the highest nuclear export of CiHMGB2b, and poly(I : C) and LPS evoked the highest nucleocytoplasmic shuttling of CiHMGB1b. Overall, the nucleocytoplasmic shuttling of CiHMGB2a and CiHMGB3b was rarely induced by these challenges. Dynamic imaging uncovered that the nucleocytoplasmic GCRV-induced relocation of CiHMGB2b occurred in cells undergoing karyotheca rupture, apoptosis or proliferation. Western blot analyses were used to examine HMGB-EGFP fusion proteins in whole cell lysates, cytosol, nuclear fractions and culture medium. Further investigation demonstrated the nuclear retention of N-terminal HMG-boxes and the nucleocytoplasmic distribution of the C-terminal acidic tails. Comparative analyses of the dynamic relocation of full-length, truncated or chimeric HMGBs confirmed that the intramolecular interaction between HMG-boxes and C-tail domains mediated the nucleocytoplasmic translocation of HMGBs. These results not only provide an overall understanding of the subcellular localization of HMGBs, but also reveal the induction mechanism of the nucleocytoplasmic translocation of HMGBs by GCRV challenge, which lays a foundation for further studies on the interactions among pathogens, HMGBs and pattern recognition receptors in the innate immunity of teleosts. Keywords: grass carp (Ctenopharyngodon idella); grass carp reovirus; HMGBs; innate immunity; subcellular localization INTRODUCTION High-mobility group box (HMGB) proteins are abundant non-histone chromatin components implicated in major DNA transactions. In mammals, there are four family members (HMGB1-4), of which HMGB1, 2 and 3 are characterized by two DNA-binding domains (HMG-box A and B) and a Cterminal acidic tail domain and HMGB4 possesses two HMG-boxes but lacks the acidic tail. 1 In some teleosts, such as fugu (Takifugu), medaka (Oryzias latipes), Tetraodon and stickleback, two paralogous genes were detected for HMGB1 and HMGB2 but not for HMGB3. 2 However, in zebrafish (Danio rerio), salmon (Oncorhynchus), carp (Cyprinus carpio) 2 and grass carp (Ctenopharyngodon idella), 3-5 two paralogs are present within each of the HMGB subfamilies (HMGB1,

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Rao

Yang

et al. 2014

Cell Mol Immunol

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“…Extracellular HMGB1 functions as a proinflammatory cytokine-like molecule by direct binding to TLR4 or indirectly binding with other molecules (41). In addition, HMGB1 can play an intracytoplasmic role as a regulator between macroautophagy and apoptosis (11,(42)(43)(44) and a sentinel molecule for viral nucleic acid sensing (45).…”

Section: Discussionmentioning

confidence: 99%

Chaperone-like Activity of High-Mobility Group Box 1 Protein and Its Role in Reducing the Formation of Polyglutamine Aggregates

Min

et al. 2013

The Journal of Immunology

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High-mobility group box 1 protein (HMGB1), which mainly exists in the nucleus, has recently been shown to function as a sentinel molecule for viral nucleic acid sensing and an autophagy regulator in the cytoplasm. In this study, we studied the chaperone-like activity of HMGB1 and found that HMGB1 inhibited the chemically induced aggregation of insulin and lysozyme, as well as the heat-induced aggregation of citrate synthase. HMGB1 also restored the heat-induced suppression of cytoplasmic luciferase activity as a reporter protein in hamster lung fibroblast O23 cells with expression of HMGB1. Next, we demonstrated that HMGB1 inhibited the formation of aggregates and toxicity caused by expanded polyglutamine (polyQ), one of the main causes of Huntington disease. HMGB1 directly interacted with polyQ on immunofluorescence and coimmunoprecipitation assay, whereas the overexpression of HMGB1 or exogenous administration of recombinant HMGB1 protein remarkably reduced polyQ aggregates in SHSY5Y cells and hmgb1−/− mouse embryonic fibroblasts upon filter trap and immunofluorescence assay. Finally, overexpressed HMGB1 proteins in mouse embryonic primary striatal neurons also bound to polyQ and decreased the formation of polyQ aggregates. To this end, we have demonstrated that HMGB1 exhibits chaperone-like activity and a possible therapeutic candidate in polyQ disease.

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“…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 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].…”

Section: Introductionmentioning

confidence: 99%

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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HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses

Cited by 602 publications

References 33 publications

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Chaperone-like Activity of High-Mobility Group Box 1 Protein and Its Role in Reducing the Formation of Polyglutamine Aggregates

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

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