Alternative titles; symbols
HGNC Approved Gene Symbol: HSPA1A
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,815,543-31,817,942 (from NCBI)
A number of organisms, such as Drosophila, respond to elevated temperature by synthesizing a small number of specific proteins. This phenomenon occurs also in yeast and in cultured HeLa cells. Exposure of HeLa cells to a temperature of 45 degrees C for 10 minutes leads to an increased synthesis of at least 3 sets of proteins with molecular masses of about 100,000, 72,000-74,000, and 37,000 daltons (Slater et al., 1981). The phenomenon is blocked by actinomycin D, suggesting transcriptional control. In vitro translation of cytoplasmic RNA from heat-shocked cells, followed by 2-D gel analysis of the translation products, shows that the major 72,000- to 74,000-dalton band consists of 7 polypeptides, designated alpha, alpha-prime, beta, gamma, delta, epsilon, and zeta. The increase in synthesis of the heat-shock proteins begins soon after heat treatment but does not reach a maximum until 2 hours later. The pattern of induction suggests coordinate regulation. To study this, Cato et al. (1981) cloned the cDNA sequences encoding the beta, gamma, delta, and epsilon heat-shock polypeptides. Hickey et al. (1986) isolated cDNA clones representing at least 5 distinct heat-inducible mRNAs in human cells.
Milner and Campbell (1990) determined that the HSPA1A gene encodes a predicted 641-amino acid protein. By Northern blot analysis of HeLa cell RNA, they detected an approximately 2.4-kb HSPA1A transcript that was constitutively expressed at low levels and was induced following heat shock.
While the function of the ubiquitous, highly conserved heat-shock proteins was unknown, an intriguing relationship between expression of heat-shock proteins and transformation had been observed. Pelham (1986) speculated on the function of heat-shock proteins.
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 (601324), which complexes with heat-shock proteins HSC70 (600816) and HSP70, translation initiation factor EIF4G (600495), and poly(A)-binding protein (604679). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Laroia et al. (1999) found that 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.
During adenovirus late infection, or heat shock of cells, translation of most capped cellular mRNAs is inhibited and adenovirus late mRNAs are translated by a mechanism called ribosome shunting. In shunting, ribosomes are loaded onto mRNA by a cap-dependent process, but then shunt or bypass large segments of the mRNA before initiating translation at a downstream AUG. Ribosome shunting is mediated by the 5-prime noncoding region of adenovirus mRNAs, called the tripartite leader, which shares striking complementarity to 18S rRNAs. Yueh and Schneider (2000) found that the 5-prime noncoding region of human HSP70 mRNA contains an element related to the adenovirus tripartite leader sequence. This element promoted ribosome shunting for HSP70 expression during heat shock when cap-dependent protein synthesis was blocked.
Unfolded PAELR (602583) is a substrate of the E3 ubiquitin ligase parkin (602544). Accumulation of PAELR in the endoplasmic reticulum (ER) of dopaminergic neurons induces ER stress leading to neurodegeneration. Imai et al. (2002) showed that CHIP (607207), HSP70, parkin, and PAELR formed a complex in vitro and in vivo. The amount of CHIP in the complex increased during ER stress. CHIP promoted the dissociation of HSP70 from parkin and PAELR, thus facilitating parkin-mediated PAELR ubiquitination. Moreover, CHIP enhanced parkin-mediated in vitro ubiquitination of PAELR in the absence of HSP70. CHIP also enhanced the ability of parkin to inhibit cell death induced by PAELR. The authors concluded that CHIP is therefore a mammalian E4-like molecule that positively regulates parkin E3 activity.
HSPs are molecular chaperones that control protein folding and prevent aggregation of proteins. They complex with peptides and bind to dendritic cells (DCs) and macrophages before being internalized in a receptor-dependent manner. HSPs then colocalize with MHC class I molecules to initiate protective and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Using flow cytometric and Western blot analyses with binding inhibition assays, Delneste et al. (2002) found that HSP70 bound LOX1 (OLR1; 602601), but not other scavenger receptors tested, on both DCs and macrophages to gain access to the MHC class I pathway to initiate CTL responses.
Young et al. (2003) showed that the cytosolic chaperones HSP90 (140571) and HSP70 dock onto a specialized tetratricopeptide (TPR) domain in the import receptor TOMM70 (606081) at the outer mitochondrial membrane. This interaction served to deliver a set of preproteins to the receptor for subsequent membrane translocation dependent on the HSP90 ATPase. Disruption of the chaperone/TOMM70 recognition inhibited the import of these preproteins into mitochondria. Young et al. (2003) proposed a mechanism in which chaperones are recruited for a specific targeting event by a membrane-bound receptor.
TIM44 (605058), a peripheral inner membrane protein, tethers mitochondrial HSP70 to the import channel. Liu et al. (2003) showed that regulated interactions maximized occupancy of the active, ATP-bound mitochondrial HSP70 at the channel through its intrinsic high affinity for TIM44, as well as through release of ADP-bound mitochondrial HSP70 from TIM44 by the cofactor MGE1. A model peptide substrate rapidly released mitochondrial HSP70 from TIM44, even in the absence of ATP hydrolysis. In vivo, the analogous interaction of translocating polypeptide would release mitochondrial HSP70 from the channel. Consistent with the ratchet model of translocation, subsequent hydrolysis of ATP would trap the polypeptide, driving import by preventing its movement back toward the cytosol.
Shimizu et al. (1999) found that peripheral blood mononuclear cells of 18 major depression patients expressed a short HSPA1A transcript that utilized exon 1 rather than exon 2, which is found in the more common HSPA1A transcript. No protein was associated with expression of this short HSPA1A mRNA, possibly due to lack of a TATA box or loss of internal ribosome binding sites.
Becker et al. (2002) found that mouse macrophages expressing Cd40 (109535) specifically bound and internalized human HSP70 with its bound peptide. Binding of HSP70-peptide complex to the exoplasmic domain of Cd40 was mediated by the N-terminal nucleotide-binding domain of HSP70 in its ADP state. Binding between HSP70 and Cd40 increased in the presence of the peptide substrate, and binding induced signaling via p38 (600289). Becker et al. (2002) concluded that CD40 is a cochaperone-like receptor that mediates the uptake of exogenous HSP70-peptide complexes by macrophages and dendritic cells.
Ficker et al. (2003) demonstrated that the cytosolic chaperones HSP70 and HSP90 interact directly with the core-glycosylated form of the wildtype HERG (152427) gene product (the alpha subunit of the I(Kr) cardiac potassium channel) present in the ER, but not the fully glycosylated, cell surface form. Trafficking-deficient mutants remained tightly associated with HSP70 and HSP90 in the ER, whereas a nonfunctional but trafficking HERG was released from the chaperones during maturation, comparable to the wildtype. Ficker et al. (2003) concluded that HSP90 and HSP70 are crucial for the maturation of wildtype HERG as well as the retention of trafficking-deficient HERG mutants.
Kalia et al. (2004) demonstrated that rat Bag5 (603885) directly interacts with Hsp70 and parkin (602544). Bag5 inhibited both Hsp70-mediated refolding of misfolded proteins and parkin E3 ubiquitin ligase activity, and enhanced the sequestration of parkin in protein aggregates. In rats, overexpression of Bag5 resulted in increased death of dopaminergic neurons compared to controls, whereas overexpression of an inhibitory mutant Bag5 resulted in increased dopaminergic survival. Kalia et al. (2004) concluded that Bag5 is a negative regulator of both Hsp70 and parkin function that sensitizes dopaminergic neurons to injury-induced death and thus promotes neurodegeneration.
Using recombinant human and bovine proteins for pull-down assays, Okada et al. (2004) showed that the Ca(2+)-binding protein S100A1 (176940), but not calmodulin (see 114180), interacted with heat-shock chaperone components HSP90, HSP70, FKBP52 (FKBP4; 600611), and CYP40 (PPID; 601753). Coimmunoprecipitation studies confirmed the interactions. S100A1 contributed to protein refolding in the HSP70/HSP90 multichaperone complex.
Rohde et al. (2005) found that cancer cells depleted of HSP70 and HSP70-2 (HSPA2; 140560) by small interfering RNA displayed strikingly different morphologies (detached and round vs flat senescent-like), cell cycle distribution (G2/M vs G1 arrest), and gene expression profiles. Concomitant depletion of HSP70 and HSP70-2 had a synergistic antiproliferative effect on cancer cells.
Qian et al. (2006) demonstrated that CHIP (607207) not only enhances HSP70 induction during acute stress, but also mediates its turnover during the stress recovery process. Central to this dual phase regulation is its substrate dependence: CHIP preferentially ubiquitinates chaperone-bound substrates, whereas degradation of HSP70 by CHIP-dependent targeting to the ubiquitin-proteasome system occurs when misfolded substrates have been depleted. Qian et al. (2006) concluded that the sequential analysis of the CHIP-associated chaperone adaptor and its bound substrate provides an elegant mechanism for maintaining homeostasis by tuning chaperone levels appropriately to reflect the status of protein building within the cytoplasm.
Ribeil et al. (2007) demonstrated that during erythroid differentiation but not apoptosis, the chaperone protein Hsp70 protects GATA1 (305371) from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 colocalizes and interacts with GATA1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage of GATA1. In an in vitro assay, Hsp70 protected GATA1 from caspase-3 (CASP3; 600636)-mediated proteolysis through its peptide-binding domain. Ribeil et al. (2007) used RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin. This led to GATA1 cleavage, a decrease in hemoglobin content, downregulation of the expression of the antiapoptotic protein Bcl-XL (see 600039), and cell death by apoptosis. These effects were abrogated by the transduction of a caspase-resistant GATA1 mutant. Thus, Ribeil et al. (2007) concluded that in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active CASP3 from cleaving GATA1 and inducing apoptosis.
Chung et al. (2008) found that obese insulin-resistant patients had reduced HSP72 protein expression and increased JNK (see JNK1, 601158) phosphorylation in skeletal muscle. Overexpression of HSP72 in skeletal muscle and globally in mice using heat shock therapy, transgenic overexpression, or pharmacologic means resulted in protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. The protection was tightly associated with the prevention of JNK phosphorylation. Chung et al. (2008) concluded that HSP72 plays an essential role in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.
Kirkegaard et al. (2010) showed that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential cofactor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (trp90 to phe), as well as the pharmacologic and genetic inhibition of ASM, effectively revert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease A (257200) and B (607616), severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase-1 gene (SMPD1; 607616) encoding ASM, is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Kirkegaard et al. (2010) concluded that, taken together, their data opened exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.
Using an immunohistochemical screen on human tissue sections, Fong et al. (2015) identified Hsp70 as an endogenous ligand of SIGLEC5 (604200) and SIGLEC14 (618132), even though Hsp70 is not a glycosylated protein. Further analyses demonstrated that Hsp70 interacted with the V-set domains of SIGLEC5 and SIGLEC14. In monocytic cells, Hsp70 delivered an antiinflammatory response through SIGLEC5, but a proinflammatory response through SIGLEC14. However, monocytes from individuals homozygous for the SIGLEC14-null allele displayed an immune response identical to the immunosuppressive response of SIGLEC5, with Hsp70 invoking an antiinflammatory response instead of a proinflammatory response.
By immunoprecipitation and mass spectrometric analyses, Ding et al. (2015) identified RAI16 (FHIP2B; 620230) as a protein kinase A (PKA)-anchoring protein (AKAP) that interacted directly with the type II regulatory subunit of PKA (PKA-RII-alpha) (PRKAR2A; 176910) in HEK293T cells. RAI16 also interacted with HSP70 and 4-3-3-theta (YWHAQ; 609009). RAI16 interacted with the C terminus of HSP70 and mediated phosphorylation of HSP70 at ser486 via PKA. Moreover, RAI16 was phosphorylated itself at ser325 by PKA. Phosphorylated RAI16 interacted with a central portion of 14-3-3-theta, and phosphorylation of RAI16 was required for its binding to 14-3-3-theta. By binding to RAI16, 14-3-3-theta inhibited phosphorylation of HSP70 by PKA.
Song et al. (2016) found that treatment of SH-SY5Y cells with glutamate induced translocation of HSP70 and VHR (DUSP3; 600183) from cytoplasm to nucleus, where they interacted to enhance VHR phosphatase activity. Nuclear translocation of HSP70 by glutamate was necessary for its interaction with VHR and was facilitated by VRK3 (619771), as VRK3 also interacted with HSP70. Glutamate treatment induced ERK (see 601795) activity in SH-SY5Y cells, which in turn transcriptionally upregulated expression of HSP70 and VRK3 to enhance phosphatase activity of VHR in the nucleus to prevent cell death that could be caused by excitotoxicity resulted from persistent ERK activity. The same protective effect against glutamate excitotoxicity-induced cell death was confirmed in mouse cortical neurons by in vitro analysis and by in vivo analysis with Vrk3-deficient mice. Furthermore, analysis with brain lysates from human patients showed that increased expression and nuclear localization of HSP70 suppressed beta-amyloid protein (104760) accumulation and neuronal cell death in brains of Alzheimer disease (AD; 104300) and Parkinson disease (PD; 168600) patients.
Milner and Campbell (1990) reported that the HSPA1A gene, which they called HSP70-1, lacks introns.
Shimizu et al. (1999) determined that the HSPA1A gene contains 3 exons. Exons 1 and 2 are alternatively spliced onto exon 3, which is the protein-coding exon. TATA, CCAAT, and GC boxes are present only in exon 2, while E boxes are present only in exon 1. The exons also differ in many of the available transcription factor binding sites.
Using a cloned genomic HSP70 DNA sequence, Goate et al. (1987) demonstrated by somatic cell hybrid and RFLP analyses that there are at least 3 distinct HSP70 loci in the human genome, one of which is located on chromosome 6. By Southern analysis, protein gels of Chinese hamster-human somatic cell hybrids, and in situ hybridization, Harrison et al. (1986, 1987) demonstrated that functional genes encoding HSP70 map to human chromosomes 6, 14 (HSPA2; 140560), 21, and at least one other chromosome. The majority of the grains on chromosome 6 were localized on the short arm with a peak in the region 6p22-p21.3. On chromosome 14, the localization was 14q22-q24. Both of these regions contain fragile sites. Two heat-shock genes (140555, 140556) are located on 1q (Leung et al., 1992), possibly in the area of other components of the complement system, the regulators of complement activation (RCA; 120830, etc.), clustered on 1q32. Thus, gene duplication events may have played a role in the evolution of heat-shock genes.
Sargent et al. (1989) demonstrated a duplicated HSP70 locus between the complement and tumor necrosis factor genes within the human major histocompatibility complex (MHC) on 6p21.3, 12 kb apart from each other and 92 kb telomeric to the C2 gene. Gaskins et al. (1990) demonstrated that an Hsp70 gene is located in the MHC of the mouse also. Milner and Campbell (1990) found within the human MHC not only 2 copies of the HSP70 gene (HSPA1A and HSPA1B; 603012) but also a third homolog, HSP70-HOM (HSPA1L; 140559).
Grosz et al. (1992) concluded that the bovine HSP70-1 and HSP70-2 genes are homologous to human HSPA1A and HSPA1L because they are located on bovine chromosome 23 and show synteny with loci on 6p in the human.
Milner and Campbell (1992) investigated the presence of sequence variation in the HSPA1A gene among different HLA haplotypes. They found only very limited sequence variation, which did not result in amino acid substitutions.
Associations Pending Confirmation
For discussion of a possible association between variation in the HSPA1A gene and noise-induced hearing loss, see 613035.
Spinocerebellar ataxia type 1 (SCA1; 164400) is a triplet repeat disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brainstem neurons. In SCA1 and other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions. Because these nuclear inclusions accumulate molecular chaperones, ubiquitin, and proteasomal subunits (all components of the cellular protein refolding and degradation machinery), the authors hypothesized that protein misfolding and impaired protein clearance may underlie the pathogenesis of polyglutamine diseases. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model by reducing protein aggregation, Cummings et al. (2001) crossbred SCA1 mice with mice overexpressing inducible HSP70. Although the amount of nuclear inclusions in Purkinje cells persisted, physiologic and histopathologic analysis revealed that high levels of HSP70 appeared to afford protection against neurodegeneration and preserved dendritic arborization in the cerebellum.
Gehrig et al. (2012) showed that increasing the expression of intramuscular Hsp72 preserves muscle strength and ameliorates the dystrophic pathology in 2 mouse models of muscular dystrophy. Treatment with BGP-15, a pharmacologic inducer of Hsp72 that can protect against obesity-induced insulin resistance, improved muscular architecture, strength, and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe kyphosis, muscle weakness, and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles, and extended life span. Gehrig et al. (2012) found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA; 108730) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with Serca to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased Serca activity in dystrophic skeletal muscles. Gehrig et al. (2012) concluded that their results provided evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell, and pharmacologic therapies.
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