Disease relevance of HSPA8

• CHIP could rescue phosphorylated tau-induced cell death, and therefore the CHIP-Hsc70 complex may provide a new therapeutic target for the tauopathies [1].
• BAG-i expression in human breast cancer: interrelationship between BAG-1 RNA, protein, HSC70 expression and clinico-pathological data [2].
• Nuclear hsp73 expression quantitatively increased in osteosarcoma cells [3].
• To further understand the mechanism of action of 4PBA, we tested the hypothesis that 4PBA modulates the targeting of DeltaF508-CFTR for ubiquitination and degradation by reducing the expression of Hsc70 in cystic fibrosis epithelial cells [4].
• Western blotting analysis showed that hsc70 and hsp70 were both expressed in five gastric cancer cell lines [5].

Psychiatry related information on HSPA8

• Therefore, we purified a preparation of HSP70/HSC70 from bovine muscle and used it in a model of Huntington's disease [6].

High impact information on HSPA8

• We demonstrate that purified light chains and synthetic peptides derived from their sequences bind hsc70 to stimulate ATP hydrolysis [7].
• Our results show that LCa is more important for interactions with hsc70 than is LCb and suggest a model in which the LCa conformation regulates coated vesicle uncoating [7].
• These differences correlate with high sequence divergence in the proline- and glycine-rich region (residues 47-71) that forms the hsc70 binding site [7].
• In lymphoblastoid cells homozygous for these same HLA-DRB1 alleles the constitutive 70-kD HSP, HSP73, that targets selected proteins to lysosomes coprecipitated with HLA-DR [8].
• Thus the QKRAA and RRRAA amino acid motifs of HLA-DR mediate binding of HLA-DR to HSP73 [8].

Chemical compound and disease context of HSPA8

• Here, we report a detailed study on the regulation of Hsc70 by ethanol in NG108-15 neuroblastoma x glioma cells [9].
• Reduction of HSP70 and HSC70 heat shock mRNA induction by pentobarbital after transient global ischemia in gerbil brain [10].
• Treatment with extracellular HSP70/HSC70 protein can reduce polyglutamine toxicity and aggregation [6].
• Reduction of HSP70 and HSC70 mRNA inductions by bifemelane hydrochloride after transient ischemia in gerbil brain [11].
• Sequencing demonstrated mutation in the NH2-terminal ATPase domain of HSC70 in 2 of 15 sporadic breast carcinomas examined [12].

Biological context of HSPA8

• Upregulation of a group of heat shock proteins (HSPA1A, HSPA2 and HSPA8) in chondrons was validated by real time reverse transcription polymerase chain reaction (RT-PCR) [13].
• Our results reveal an unexpected diversity in the regulation of Hsc70 and raise the possibility that the observed anti-apoptotic function of BAG-1 may be exerted through a modulation of the chaperone activity of Hsc70 on specific protein folding and maturation pathways [14].
• The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis [15].
• Heat shock cognate protein 70 (Hsc70) serves nuclear transport of several proteins as a molecular chaperone [16].
• We have recently identified a novel variant of human Hsc70, heat shock cognate protein 54 (Hsc54), that lacks amino acid residues 464-616 in the protein binding and variable domains of Hsc70 [16].

Anatomical context of HSPA8

• Uncoating of clathrin-coated vesicles is mediated by the heat shock cognate protein, hsc70, and requires clathrin light chains (LCa and LCb) and ATP hydrolysis [7].
• We propose that dj2 is the functional partner DnaJ homologue of hsc70 in the mammalian cytosol [17].
• Preparations of HSP70, which consisted mainly of the constitutively expressed HSP73, induced only marginal cytokine release from monocytes [18].
• These results suggest that GAK, in conjunction with Hsc70, not only uncoats clathrin-coated vesicles and induces clathrin exchange on clathrin-coated pits, but also mediates binding of clathrin and adaptors to the plasma membrane and the trans-Golgi network [19].
• HSC70 recovered the luciferase activity in the presence of reticulocyte lysate as a source of cochaperones [20].

Associations of HSPA8 with chemical compounds

• BAG-1 also interacts with several steroid hormone receptors which require the molecular chaperones Hsc70 and Hsp90 for activation [14].
• In contrast, the nucleocytoplasmic localization of Hsc70 was not affected by the same mutation of NES or leptomycin B [16].
• We further found that Hsc54 contains a functional leucine-rich nuclear export signal (NES, (394)LDVTPLSL(401)) which is differently situated from the previously proposed NES in Saccharomyces cerevisiae Ssb1p [16].
• Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR [4].
• Similar to Hop, CyP40 was shown not to influence the adenosine triphosphatase activity of Hsc70 [21].

Physical interactions of HSPA8

• The earliest stage at which Hdj-2/Hsc70 could bind CFTR translation intermediates coincided with the expression of NBD1 in the cytosol [15].
• Although peptides corresponding to the C-terminal region of p53 also contain potential binding sites, p53 proteins with C-terminal deletions are capable of binding to Hsc70, indicating that this region is not required for complex formation [22].
• HspBP1 attenuates the ubiquitin ligase activity of CHIP when complexed with Hsc70 [23].
• Hsc70 is among the proteins coimmunoprecipitated with stathmin, and it is the main protein retained specifically on stathmin-Sepharose beads identified by one- and two-dimensional electrophoresis and immunoblots [24].
• These experiments show a profound effect of heat shock on the structure and stability of HSF-1 complexes during nuclear localization and support the hypothesis that HSC70 binding may control HSF-1 function [25].

Enzymatic interactions of HSPA8

• A putative step in the CFTR folding pathway catalyzed by Hdj-2/Hsc70 is the formation of an intramolecular NBD1-R-domain complex [15].

Regulatory relationships of HSPA8

• Thus, BAG-1 regulates the Hsc70 ATPase in a manner contrary to the Hsc70-interacting protein Hip, which stabilizes the ADP-bound state [14].
• Bovine serum albumin (BSA)-Sepharose did not bind Hsc70, and anti-stathmin antisera specifically inhibited the interaction of Hsc70 with stathmin-Sepharose [24].
• An additional mechanism for unmasking the NES may regulate nucleocytoplasmic trafficking of Hsc70 [16].
• 4PBA downregulates protein and mRNA expression of the heat shock cognate protein HSC70 (the constitutively expressed member of the 70-kDa heat shock protein family) by approximately 40-50% and decreases formation of a HSC70-DeltaF508 CFTR complex that may be important in the intracellular degradation of DeltaF508 CFTR [26].
• Hsp70 was induced in fibroblasts upon heavy metal exposure concentrations as low as 0.01 microM whereas hsc70 expression was induced upon organochlorine exposure concentrations as low as 0.001 microM [27].
• All combinations of DJA1 or DJA2 with the three NEFs stimulated the Hsc70 ATPase rate, although Hsp110 became less effective with increasing concentrations [28].

Other interactions of HSPA8

• Here we show that BAG-1 is a regulator of the Hsc70 chaperone [14].
• Unexpectedly, dj2, but not dj1, together with hsc70 refolded the protein efficiently [17].
• An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators [29].
• We have screened a library of overlapping biotinylated peptides, spanning the entire human p53 sequence, for binding to the HSP70 proteins, Hsc70 and DnaK [22].
• We propose that GAK is a required cofactor for the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells [30].

Analytical, diagnostic and therapeutic context of HSPA8

• Flow cytometric and Western blot analyses using various cells showed that MAb 20-202S specifically bound to the HSPA8 protein on the surface of Miz-hES1, contrary to other anti-HSP70 antibodies examined [31].
• Immunoprecipitations with antibodies against either the heat-shock cognate protein 70 (hsc70) or heat-shock protein 90 (hsp90) showed the presence of a phosphoprotein complex in 32P-labeled, resting human platelets [32].
• Immunohistochemistry was used to examine the expression of BAG-1 and HSC70 in 160 cases of invasive breast cancer [2].
• Two-dimensional gel electrophoresis of cytosolic proteins from mature human erythrocytes combined with immunoblotting revealed the presence of a group of heat shock proteins (HSPs) that included two molecular chaperons of the HSP70 family (HSX70, inducible; HSC70, constitutively expressed) and HSP90 [33].
• Immunoprecipitation with Hsc70-specific antiserum demonstrated that Hsc70 and CFTR associated under control conditions and that treatment with 4PBA reduced these complexes [4].

References