Alternative titles; symbols
HGNC Approved Gene Symbol: HSPA8
Cytogenetic location: 11q24.1 Genomic coordinates (GRCh38) : 11:123,057,489-123,062,462 (from NCBI)
The family of approximately 70-kD heat-shock proteins, HSP70 (see 140550), contains both heat-inducible and constitutively expressed members, the latter of which are sometimes called heat-shock cognate proteins (HSCs). By screening a human genomic library with Drosophila hsp70 and hsc70 cDNAs, Dworniczak and Mirault (1987) isolated the HSPA8 gene, which they called HSC70. Using HSPA8 genomic sequence to screen a human cDNA library derived from a hepatic metastasis that originated from a pancreatic gastrinoma, the authors cloned HSPA8 cDNAs. The HSPA8 gene contains 9 exons and spans 5 kb. The deduced HSPA8 protein has 646 amino acids and a predicted molecular mass of 70,899 Da. In vitro translation of HSPA8 RNA produced a polypeptide that migrated as a 71-kD protein in SDS-polyacrylamide gels. HSPA8 RNA and protein were moderately abundant in unstressed HeLa cells and were only minimally induced by heat. Dworniczak and Mirault (1987) noted that HSPA8 is likely the constitutively expressed 71-kD heat-shock protein that is identical to uncoating ATPase (Ungewickell, 1985; Chappell et al., 1986), an enzyme that releases clathrin from coated vesicles. They identified 2 distinct HSPA8-related processed pseudogenes.
Tavaria et al. (1995) stated that HSPA8 (also known as HSP73) plays an important role in cells by transiently associating with nascent polypeptides to facilitate correct folding. The protein folding process involves other constitutively expressed heat-shock proteins, such as HSP60 (HSPD1; 118190), HSP90 (HSPCA; 140571), and GRP78 (138120), which have collectively been termed chaperones. Chaperones are also involved in maintaining proteins in a semifolded state that enables translocation through the mitochondrial and endoplasmic reticulum membranes. HSP73 also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell.
Using a yeast 2-hybrid assay, Hohfeld et al. (1995) showed that rat Hip (ST13; 606796) bound Hsc70. One Hip oligomer bound the ATPase domains of at least 2 Hsc70 molecules, and binding was dependent on activation of the Hsc70 ATPase by Hsp40 (DNAJB1; 604572). Hip stabilized the ADP-bound form of Hsc70, which had a high affinity for a test protein substrate. Hohfeld et al. (1995) concluded that HIP contributes to interactions of HSC70 with target proteins through its own chaperone activity.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1, which complexes with heat-shock proteins HSC70 and HSP70, translation initiation factor EIF4G (600495), and poly(A)-binding protein (PABP, or PABPC1; 604679). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 (314370), all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway (Laroia et al., 1999).
BIM (BCL2L11; 603827) is an apoptotic factor that regulates total blood cell number. Matsui et al. (2007) uncovered a molecular mechanism for cytokine-mediated posttranscriptional regulation of Bim mRNA by Hsc70 in mouse pro-B cell lines. In the absence of Il3 (147740), Hsc70 formed a complex with Hsp40 and Hip, and this complex, in association with Eif4g and Pabp, formed a high-stability complex with Bim mRNA that protected it from ribonucleases. Il3 destabilized Bim mRNA and promoted cell survival by reducing binding of Hsc70 to Bim mRNA by promoting interaction of Hsp70 with Bag4 (603884) and Chip (STUB1; 607207) via the Ras (HRAS; 190020) signaling pathway.
CD14 (158120) and lipopolysaccharide (LPS)-binding protein (LBP; 151990) are major receptors for LPS; however, binding analyses and TNF production assays have suggested the presence of additional cell surface receptors, designated LPS-associated proteins (LAPs), that are distinct from CD14, LBP, and the Toll-like receptors (see TLR4; 603030). Using affinity chromatography, peptide mass fingerprinting, and fluorescence resonance energy transfer, Triantafilou et al. (2001) identified 4 diverse proteins, heat shock cognate protein (HSPA8), HSP90A, chemokine receptor CXCR4 (162643), and growth/differentiation factor-5 (GDF5; 601146), on monocytes that form an activation cluster after LPS ligation and are involved in LPS signal transduction. Antibody inhibition analysis suggested that disruption of cluster formation abrogates TNF release. Triantafilou et al. (2001) proposed that heat shock proteins, which are highly conserved from bacteria to eukaryotic cells, are remnants of an ancient system of antigen presentation and defense against microbial pathogens.
Tobaben et al. (2001) showed that rat Csp (DNAJC5; 611203) interacted with Sgt (SGTA; 603419) and Hsc70 in a complex located on the synaptic vesicle surface. The complex functioned as an ATP-dependent chaperone that reactivated a denatured substrate. Sgt overexpression in cultured rat hippocampal neurons inhibited neurotransmitter release, suggesting that the Csp/Sgt/Hsc70 complex is important for maintenance of a normal synapse.
Hundley et al. (2005) reported that ribosome-associated molecular chaperones have been maintained throughout eukaryotic evolution, as illustrated by MPP11 (605502), the human ortholog of the yeast ribosome-associated J protein Zuo. When expressed in yeast, MPP11 partially substituted for Zuo by partnering with the multipurpose Hsp70 Ssa, the homolog of mammalian Hsc70. Hundley et al. (2005) proposed that in metazoans, ribosome-associated MPP11 recruits the multifunctional soluble Hsc70 to nascent polypeptide chains as they exit the ribosome.
Cystic fibrosis (219700) arises from misfolding and premature degradation of CFTR (602421) containing a deletion of phe508 (delF508; 602421.0001). Younger et al. (2006) identified an endoplasmic reticulum (ER) membrane-associated ubiquitin ligase complex containing the E3 RMA1 (RNF5; 602677), the E2 UBC6E (UBE2J1; 616175), and derlin-1 (DERL1; 608813) that cooperated with the cytosolic HSC70/CHIP E3 complex to triage CFTR and delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could recognize folding defects in delF508 coincident with translation, whereas CHIP appeared to act posttranslationally. A folding defect in delF508 detected by RMA1 involved the inability of the second membrane-spanning domain of CFTR to productively interact with N-terminal domains. Younger et al. (2006) concluded that the RMA1 and CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to monitor the folding status of CFTR and delF508.
Using mass spectrometry and adult mouse brain proteins immobilized on nitrocellulose, Leshchyns'ka et al. (2006) found that the intracellular domain of the cell adhesion molecule Chl1 (607416) bound Hsc70. Mutation analysis revealed that an HPD motif conserved in mouse and human CHL1 was required for the interaction. ADP potentiated interaction between Chl1 and Hsc70. Chl1 accumulated in the presynaptic plasma membrane and recruited Hsc70 in an ADP-dependent manner. In response to synapse activation, Chl1 was targeted to synaptic vesicles by endocytosis. Chl1 deficiency in Chl1 -/- neurons or disruption of the Chl1-Hsc70 interaction by the isolated HPD peptide caused reduced levels of Hsc70 on synaptic vesicles, reduced clathrin release from clathrin-coated synaptic vesicles, and reduced marker dye uptake and release in synaptic boutons.
In a neuronal cell line, Yang et al. (2009) found that chaperone-mediated autophagy regulated the activity of myocyte enhancer factor 2D (MEF2D; 600663), a transcription factor required for neuronal survival. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70, and undergo degradation. Inhibition of chaperone-mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm. MEF2D levels were increased in the brains of alpha-synuclein transgenic mice and patients with Parkinson disease. Wildtype alpha-synuclein and a Parkinson disease-associated mutant (A53T, 163890.0001) disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, Yang et al. (2009) concluded that chaperone-mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson disease.
Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation (602421.0001) from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP-UBCH5C and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology.
Scott et al. (2012) found that the 3-prime UTR of rat and human HSC70 contains recognition sequences predicted to bind mature microRNAs (miRNAs) arising from both the 5-prime and 3-prime ends of the MIR3120 (614722) precursor stem-loop sequence. Overexpression of rat Mir3120 or a vector containing repeats of the MIR3120 recognition sequence reduced expression of rat Hsc70 and a human HSC70 reporter gene in rat neuronal cells. Mir3120 also reduced expression of the HSC70 cochaperone auxilin (DNAJC6; 608375), and it reduced surface content of clathrin-coated particles in hippocampal and cortical neurons.
Using immunoaffinity-mass spectrometric and immunoprecipitation analyses, Choi et al. (2014) showed that DNAJC12 (606060) interacted strongly with HSC70 in human LNCaP prostate cancer cells. Choi et al. (2014) concluded that DNAJC12 has a role in regulation of HSC70 function.
Kretschmann et al. (2019) found that intercellular transfer of mouse and human Y chromosome antigen DBY (DDX3Y; 400010) required interaction with HSC70 through the conserved KFERQ-like motif of DBY. After binding HSC70, cytosolic DBY was recruited to extracellular vesicles of endosomal origin. These vesicles functioned as antigen carriers between viable cells to deliver DBY in a manner independent of cell-cell contact.
By Southern blot analysis, Tavaria et al. (1995) demonstrated that the HSP73 gene is located on human chromosome 11. Fluorescence in situ hybridization further localized HSP73 to 11q23.3-q25.
Chappell, T. G., Welch, W. J., Schlossman, D. M., Palter, K. B., Schlesinger, M. J., Rothman, J. E. Uncoating ATPase is a member of the 70 kilodalton family of stress proteins. Cell 45: 3-13, 1986. [PubMed: 2937542] [Full Text: https://doi.org/10.1016/0092-8674(86)90532-5]
Choi, J., Djebbar, S., Fournier, A., Labrie, C. The co-chaperone DJNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress. Cell Stress Chaperones 19: 439-446, 2014. [PubMed: 24122553] [Full Text: https://doi.org/10.1007/s12192-013-0471-6]
Dworniczak, B., Mirault, M.-E. Structure and expression of a human gene coding for a 71 kd heat shock 'cognate' protein. Nucleic Acids Res. 15: 5181-5197, 1987. [PubMed: 3037489] [Full Text: https://doi.org/10.1093/nar/15.13.5181]
Hohfeld, J., Minami, Y., Hartl, F.-U. Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle. Cell 83: 589-598, 1995. [PubMed: 7585962] [Full Text: https://doi.org/10.1016/0092-8674(95)90099-3]
Hundley, H. A., Walter, W., Bairstow, S., Craig, E. A. Human Mpp11 J protein: ribosome-tethered molecular chaperones are ubiquitous. Science 308: 1032-1034, 2005. [PubMed: 15802566] [Full Text: https://doi.org/10.1126/science.1109247]
Hutt, D., Balch, W. E. The proteome in balance. Science 329: 766-767, 2010. [PubMed: 20705837] [Full Text: https://doi.org/10.1126/science.1194160]
Kretschmann, S., Herda, S., Bruns, H., Russ, J., van der Meijden, E. D., Schlotzer-Schrehardt, U., Griffioen, M., Na, I.-K., Mackensen, A., Kremer, A. N. Chaperone protein HSC70 regulates intercellular transfer of Y chromosome antigen DBY. J. Clin. Invest. 129: 2952-2962, 2019. [PubMed: 31205025] [Full Text: https://doi.org/10.1172/JCI123105]
Laroia, G., Cuesta, R., Brewer, G., Schneider, R. J. Control of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 284: 499-502, 1999. [PubMed: 10205060] [Full Text: https://doi.org/10.1126/science.284.5413.499]
Leshchyns'ka, I., Sytnyk, V., Richter, M., Andreyeva, A., Puchkov, D., Schachner, M. The adhesion molecular CHL1 regulates uncoating of clathrin-coated synaptic vesicles. Neuron 52: 1011-1025, 2006. [PubMed: 17178404] [Full Text: https://doi.org/10.1016/j.neuron.2006.10.020]
Matsui, H., Asou, H., Inaba, T. Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70. Molec. Cell 25: 99-112, 2007. [PubMed: 17218274] [Full Text: https://doi.org/10.1016/j.molcel.2006.12.007]
Okiyoneda, T., Barriere, H., Bagdany, M., Rabeh, W. M., Du, K., Hohfeld, J., Young, J. C., Lukacs, G. L. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329: 805-810, 2010. [PubMed: 20595578] [Full Text: https://doi.org/10.1126/science.1191542]
Scott, H., Howarth, J., Lee, Y. B., Wong, L.-F., Bantounas, I., Phylactou, L., Verkade, P., Uney, J. B. MiR-3120 is a mirror microRNA that targets heat shock cognate protein 70 and auxilin messenger RNAs and regulates clathrin vesicle uncoating. J. Biol. Chem. 287: 14726-14733, 2012. [PubMed: 22393045] [Full Text: https://doi.org/10.1074/jbc.M111.326041]
Tavaria, M., Gabriele, T., Anderson, R. L., Mirault, M.-E., Baker, E., Sutherland, G., Kola, I. Localization of the gene encoding the human heat shock cognate protein, HSP73, to chromosome 11. Genomics 29: 266-268, 1995. [PubMed: 8530083] [Full Text: https://doi.org/10.1006/geno.1995.1242]
Tobaben, S., Thakur, P., Fernandez-Chacon, R., Sudhof, T. C., Rettig, J., Stahl, B. A trimeric protein complex functions as a synaptic chaperone machine. Neuron 31: 987-999, 2001. [PubMed: 11580898] [Full Text: https://doi.org/10.1016/s0896-6273(01)00427-5]
Triantafilou, K., Triantafilou, M., Dedrick, R. L. A CD14-independent LPS receptor cluster. Nature Immun. 2: 338-345, 2001. Note: Erratum: Nature Immun. 2: 658 only, 2001. [PubMed: 11276205] [Full Text: https://doi.org/10.1038/86342]
Ungewickell, E. The 70-kd mammalian heat shock proteins are structurally and functionally related to the uncoating protein that releases clathrin triskelia from coated vesicles. EMBO J. 4: 3385-3391, 1985. [PubMed: 2868889] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb04094.x]
Yang, Q., She, H., Gearing, M., Colla, E., Lee, M., Shacka, J. J., Mao, Z. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323: 124-127, 2009. [PubMed: 19119233] [Full Text: https://doi.org/10.1126/science.1166088]
Younger, J. M., Chen, L., Ren, H.-Y., Rosser, M. F. N., Turnbull, E. L., Fan, C.-Y., Patterson, C., Cyr, D. M. Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126: 571-582, 2006. [PubMed: 16901789] [Full Text: https://doi.org/10.1016/j.cell.2006.06.041]