Disease relevance of Hsp90b1

• We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis [1].
• However, cell surface gp96 induced significant DC activations and spontaneous lupus-like autoimmune diseases, even though the development/functions of lymphocytic compartments were unaltered [2].
• Down-regulation of gp96 by Orientia tsutsugamushi [3].
• We examined the expression of GRP94 and GRP78 in embryonal carcinoma (EC) cells and during early mouse development [4].
• In contrast to these cell types, WEHI7.2 mouse lymphoma cells undergo apoptosis when treated with TG, prompting us to examine the grp78/grp94 stress response in WEHI7.2 cells [5].

High impact information on Hsp90b1

• Perforin is required for innate and adaptive immunity induced by heat shock protein gp96 [6].
• Postuptake processing of gp96-chaperoned peptides requires proteasomes and the transporters associated with antigen processing, utilizing the classical endogenous antigen presentation pathway [7].
• In addition, vaccination with irradiated cells secreting the GRP94 NH(2)-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression [1].
• Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind gp96 [8].
• Thus, we provide evidence on the mechanisms by which gp96 is participating in the cross-presentation of antigens from cellular origin [8].

Chemical compound and disease context of Hsp90b1

• GRP78 increased in a dose- and time-dependent fashion in embryonic hearts exposed to either 40 mg/dl or 80 mg/dl glucose, whereas GRP94 levels increased in hearts only after 24 h of hypoglycemia [9].
• A lower percentage of propidium-iodide positive/GFP-fluorescent myocytes co-expressing exogenous Grp94, with respect to myocytes expressing GFP alone, was observed after exposure to either A23187 (6.6% vs. 14.0%, respectively) or simulated ischemia (8.5% vs. 17.7%, respectively) [10].
• The number of necrotic cells, evaluated by propidium iodide uptake, was reduced when cells from the Grp94-overexpressing H9c2 clone were exposed to conditions simulating ischemia [10].
• Rabbit antiserum to murine gp96 detects an antigenically related Mr 96,000 cell surface glycoprotein on two cultured human melanoma cell lines, SK-MEL-13 and SK-MEL-177 [11].

Biological context of Hsp90b1

• To examine the generality of this finding, we have investigated the role of endotoxin in GRP94/gp96-elicited macrophage activation [12].
• Additional studies are required to determine whether Tra1/Grp94 or another candidate proto-oncogene in Evi12 is involved in leukemogenesis [13].
• Sequence analysis demonstrated that Evi12 is located upstream of the gene encoding the molecular chaperone Tra1/Grp94, which was previously mapped to mouse chromosome 10 and human chromosome 12q22-24 [13].
• Although a pan-specific promoter is used for transgene expression, neither the expression level nor the tissue distribution of the endogenous gp96 was altered by this maneuver [2].
• Using a bone marrow chimera approach, we further demonstrated that both DC activation and autoimmunity elicited by cell surface gp96 are dependent on the downstream adaptor protein MyD88 for signaling by Toll/IL-1 receptor family [2].

Anatomical context of Hsp90b1

• GRP94 is a molecular chaperone that carries immunologically relevant peptides from cell to cell, transferring them to major histocompatibility proteins for presentation to T cells [14].
• Vaccination of mice with GRP94/gp96, the endoplasmic reticulum Hsp90, elicits a variety of immune responses sufficient for tumor rejection and the suppression of metastatic tumor progression [12].
• Localization and significance of molecular chaperones, heat shock protein 1, and tumor rejection antigen gp96 in the male reproductive tract and during capacitation and acrosome reaction [15].
• Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity [16].
• Confocal imaging studies also demonstrate that gp96 can be induced on B cell surface without association of MHC molecules [17].

Associations of Hsp90b1 with chemical compounds

• In addition, we have shown that the interaction of the chaperoned peptides with hsc70 and gp96 is not compromised during heparin chromatography [18].
• We have isolated an expressible full-length cDNA clone encoding murine ERp99, an abundant, conserved transmembrane glycoprotein of the endoplasmic reticulum membrane [19].
• When GRP94 was present in the medium, and thus accessible to both receptor-mediated and fluid phase internalization pathways, internalization was modestly inhibited in the presence of yeast mannan, a competitive inhibitor of mannose/fucose receptor activity, and substantially inhibited by dimethylamiloride, an inhibitor of macropinocytosis [20].
• All EtRGs, including GRP94 and GRP78, showed similar ethanol concentration-dependent increases in mRNA abundance [21].
• Expression of the glucose regulated proteins (GRP78 and GRP94) is greatly increased after cells are exposed to stress agents (including A23187 and tunicamycin) which inhibit ER function [22].

Physical interactions of Hsp90b1

• HSP90 may provide antioxidant protective mechanisms against microglia/macrophages, whereas GRP94 may stabilize the astroglial cytoskeleton and participate in astroglial antioxidant mechanisms [23].

Co-localisations of Hsp90b1

• GRP94 internalized by this pathway co-localized predominately with transferrin-positive early endosomes [20].

Regulatory relationships of Hsp90b1

• The GRP78 protein is constitutively expressed in the undifferentiated F9 cells whereas the level of GRP94 is below detection limit [4].

Other interactions of Hsp90b1

• The three main immunogenic HSPs, gp96, hsp86/84, and hsc70 can be further isolated to homogeneity using additional purification methods [18].
• Low endotoxin GRP94/gp96 retained its native conformation, ligand binding activity, and in vitro chaperone function, yet did not activate macrophage NF-kappa B signaling, nitric oxide production or inducible nitric-oxide synthase production [12].
• The data demonstrate an essential role for perforin-mediated functions in the activation of innate and adaptive immunity by heat shock protein gp96-peptide complexes [6].
• The heat shock proteins (HSP) gp96, Hsp70 and Hsp60 activate professional antigen-presenting cells (APC) to secrete proinflammatory cytokines and to express costimulatory molecules [24].
• Furthermore, the novel role of gp96 in Th cell proliferation skewing its differentiation toward Th2 phenotype has also been established [17].

Analytical, diagnostic and therapeutic context of Hsp90b1

• However, Northern and Western blot analyses did not provide evidence that proviral insertion had altered the expression of Tra1/Grp94 [13].
• In the current study we compared the ability of the endoplasmic reticulum-resident HSP gp96 to prime CD4 vs CD8 cells using TCR transgenic adoptive transfer systems and soluble gp96-peptide complexes [25].
• By differential display PCR, we observed that obligate intracellular bacteria, Orientia tsutsugamushi, inhibit gp96 expression of a macrophage cell line, J774A [3].
• Both immunofluorescence and the observed association with the endoplasmic reticulum (ER) stress proteins GRP78/BiP and GRP94 indicate that the kappa chain is localized mostly in the ER [26].
• Immunoprecipitation of GRP170 with our antibody coprecipitates the GRP78 (also referred to as the B cell immunoglobulin-binding protein) and GRP94 members of this stress protein family in Chinese hamster ovary cells under stress conditions [27].

References