Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages

Yang, Yi; Liu, Bei; Dai, Jie; Srivastava, Pramod K.; Zammit, David J.; Lefrançois, Leo; Li, Zihai

doi:10.1016/j.immuni.2006.12.005

Cited by 409 publications

(483 citation statements)

References 51 publications

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“…Recently, Unc93B1, a multitransmembrane ERresident protein has been shown to associate with and deliver TLR7/9 from the ER to endosomes, where TLR7/9 recognizes their ligands [40]. In addition, gp96, an ER-resident HSP, has been shown to be a master immune chaperone for both cell surface and intracellular TLRs, including TLR1, 2, 4, 5, 7, and 9 [26]. In this study, we clarified that endosomal TLR7 and TLR9 are functionally dependent on the cytosolic chaperone Hsp90.…”

Section: Discussionmentioning

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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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: 99%

“…Furthermore, Yang et al have shown that gp96 was required to activate TLR7 and TLR9 in response to ligand stimulation [26]. Thus, gp96 acts as a master chaperone for TLR7 and TLR9 and it is indispensable for proper conformation of TLR7 and TLR9 in collaboration with PLAT4A [27].…”

Section: Hsp90 Is Essential For Cpg-a-mediated Tlr9 Translocation To mentioning

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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“…Further analysis of this mutant revealed that the major defect in this cell was in its cell surface expression of TLRs, revealing a hitherto unknown role for Gp96 in inserting the TLR proteins into the plasma membrane (Randow and Seed 2001). In a later study, a macrophage-specific Gp96-deficient mouse was created (Yang et al 2007b). Macrophages from these mice developed normally and were responsive to a range of cytokines including: IFN-γ, TNF-α and IL-1β.…”

Section: Gp96mentioning

confidence: 99%

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

Henderson

2009

Cell Stress and Chaperones

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Over the last 20 years, it has emerged that many molecular chaperones and protein-folding catalysts are secreted from cells and function, somewhat in the manner of cytokines, as pleiotropic signals for a variety of cells, with much attention being focused on the macrophage. During the last decade, it has become clear that macrophages respond to bacterial, protozoal, parasitic and host signals to generate phenotypically distinct states of activation. These activation states have been termed 'classical' and 'alternative' and represent not a simple bifurcation in response to external signals but a range of cellular phenotypes. From an examination of the literature, the hypothesis is propounded that mammalian molecular chaperones are able to induce a wide variety of alternative macrophage activation states, and this may be a system for relating cellular or tissue stress to appropriate macrophage responses to restore homeostatic equilibrium.

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“…92 Gp96 binds to and activates monocytes and neutrophils, and is essential for the subcellular localization of Toll-like receptors (TLR). 93 Therefore, in addition to promote cell invasion, the interaction of Vip with Gp96 could possibly interfere with TLR trafficking, leading to the control of the innate immune response by L. monocytogenes. 92 The aut gene was identified by comparative genomics and encodes Auto, a surface-associated GW repeat-containing protein that is absent from non-pathogenic L. innocua.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

et al. 2011

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Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages

Cited by 409 publications

References 51 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

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

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