Identification of gp96 as a Novel Target for Treatment of Autoimmune Disease in Mice

Han, Jung Min; Kwon, Nam Hoon; Lee, Jin Young; Jeong, Seung Jae; Jung, Hee Jung; Kim, Hyeong Rae; Li, Zihai; Kim, Sung Hoon

doi:10.1371/journal.pone.0009792

Cited by 40 publications

(49 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, T cells from mice treated with an HSP90 inhibitor showed reduced responsiveness to activating antigens in the collagen induced arthritis model. 25 Han et al 11 found that an inhibitor for the endoplasmic reticulum homologue of HSP90, gp96, reduced both the CD4 1 memory T cells and activated CD4 1 T cells in the spleen and lymph nodes. The effects of HSP90 inhibition on T-cell populations might be The effect of heat shock protein 90 inhibition in lupus mice SK Shimp III et al 263 explained by the fact that stimulation of the T-cell receptor leading to T-cell activation requires HSP90 to stabilize lymphocyte-specific protein tyrosine kinase (Lck) in order to initiate activation.…”

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

“…61 The inhibitor for gp96 was shown to reduce populations of mature B cells, B2201 and MHC class II1 cells. 11 However, it has also been shown that splenic plasma cells and germinal center B cells are unaffected by 17-DMAG treatment. 91 We found that only follicular B cells were affected by the HSP90 inhibition treatment, while marginal zone B cells (B1a and B1b) were not significantly affected.…”

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

“…9 In addition, HSP90 and its endoplasmic reticulum homologue, glycoprotein 96 (gp96), have been linked to autoimmunity. 3,10,11 There are several compounds in clinical trials that target HSP90 for the treatment of cancer. 12,13 The naturally occurring benzoquinoid ansamycin known as Geldanamycin (GA) has been found to be a potent and specific HSP90 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

“…25 Also, the gp96 inhibitor, (S)-methyl 2-(4,6-dimethoxypyrimidine-2-yloxy)-3-methylbutanoate, was shown to reduce the severity of SLE-like disease in transgenic mice. 11 MRL/lpr mice serve as a model to study human SLE as they exhibit similar manifestations to the human disease including glomerulonephritis (GN), vasculitis and arthritis. 26 Mesangial cells isolated from MRL/lpr mice exhibit increased sensitivity when immune-stimulated by inflammatory cytokines and chemokines such as tumor necrosis factor-a (TNFa), IL-1b, interferon-c (IFN-c) or lipopolysaccharide (LPS).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

View full text Add to dashboard Cite

Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

show abstract

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

Section: Mature B Cells Were Decreased In Mice Treated With 17-dmagmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Pharmacological inhibition of Hsp90 function has therefore emerged as a promising method to ameliorate inflammatory cascades, as it has been demonstrated in various experimental mouse models of autoimmune diseases, including autoimmune encephalomyelitis (Dello Russo et al 2006), rheumatoid arthritis (Rice et al 2008;Yun et al 2011), and systemic lupus erythematosus (Han et al 2010;Shimp et al 2012a). Our own recent research work showed that, by downregulating T cell responses, this kind of treatment is also effective in mice with the experimentally induced subepidermal autoimmune blistering skin disease epidermolysis bullosa acquisita (Kasperkiewicz et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

View full text Add to dashboard Cite

Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose-and time-dependent fashion.

show abstract

Cell membrane gp96 facilitates HER2 dimerization and serves as a novel target in breast cancer

Sun

Hou

et al. 2015

Int. J. Cancer

View full text Add to dashboard Cite

HER2 receptor dimerization is a critical step in the HER2 activation process. Here, we demonstrated that heat shock protein gp96 on cell membrane interacts with HER2, facilitates HER2 dimerization and promotes cell proliferation. Cell membrane gp96 levels were observed to correlate with HER2 phosphorylation in primary breast tumors. Finally, we provide evidence that targeting gp96 with a specific monoclonal antibody led to decreased cell growth and increased apoptosis in vitro, and suppression of tumor growth in vivo. Our work represents a new therapeutic strategy for inhibiting HER2 signaling in cancer.The heat shock protein 90 (Hsp90) family contains four members in humans, HSP90a, HSP90b, gp96 (grp94) and Trap-1. As one of the most abundant chaperones in the endoplasmic reticulum (ER), gp96 associates with client proteins and guide their maturation and assembly. In contrast to the other members of HSP90 family that may bind and activate hundreds of client proteins, gp96 has a relatively strict binding selectivity and is known to associate with only a handful of confirmed clients, including certain Toll-like receptors, 1,2 integrins, 1 insulin-like growth factors 3 and immunoglobulin. 4 A recent study by proteomic plasma membrane profiling has revealed that besides TLRs and integrins, gp96 is required for the cell surface expression of four members of LDL receptor family. To date, these gp96-regulated proteins are structurally characterized by the presence of bpropeller and leucine rich repeats (LLR), suggesting an important role of gp96 in recognizing these motifs. 5The normally ER-resident gp96 may translocate to cell membrane under bacterial infection, 6,7 or in certain tumor cells. 8,9Cell membrane-expressed gp96 is shown to correlate with malignancy in breast cancer cells. 10 However, until now few cell membrane gp96 client proteins have been identified in regulation of various cell physiological processes, including HER2 11,12 and the metalloprotease pro-ADAMTS9 (ADAMTS9). 13 The biological role of cell membrane gp96 in tumor cells deserves further investigation.Signaling through HER2 receptors is critically involved in multiple human cancers. HER2 functions as the preferred heterodimeric partner within the HER family, and HER2-containing heterodimers are characterized by slow rates of ligand dissociation and increased recycling back to the plasma membrane for reactivation, allowing potent and prolonged activation of downstream signaling pathways.14 HER2 overexpression occurs in approximately 25% of breast cancers and is related to adverse tumor characteristics and a poor prognosis in patients. 15 Due to its central roles in the regulation of HER-mediated signaling and tumorigenesis, HER2 is an ideal target for therapeutic development, including monoclonal antibodies to prevent homo or heterodimerization. [16][17][18][19] In this study, we use several approaches to examine the interaction of cell surface gp96 and HER2, and define the regulation of gp96 in HER2 dimerization and signaling. We then use an a...

show abstract

Identification of gp96 as a Novel Target for Treatment of Autoimmune Disease in Mice

Cited by 40 publications

References 43 publications

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Cell membrane gp96 facilitates HER2 dimerization and serves as a novel target in breast cancer

Contact Info

Product

Resources

About