HSPA8 (heat shock 70kDa protein 8)

2013-08-01   Tuoen Liu , Shousong Cao 





The human HSPA8 gene includes nine exons and eight introns. It is mapped into chromosome 11, 11q23.3-q25 (Sonna et al., 2002). Introns 5, 6 and 8 contain highly conserved repeats about 90 bp which code for U14 snoRNA (Chen et al., 1996). Exons 2, 3, 6, 7, and 9 code for the peptides of extremely uniform length, between 61 and 69 amino acids while exons 4, 8 and 5 code for peptides of 51, 78 and 185 amino acids, respectively. Two 150 bp direct repeats (nt 674 to nt 829 and nt 1783 to nt 1937) are 85% homologous to each other (Dworniczak and Mirault, 1987).


The gene coding for HSC70, HSPA8 affects the posttranscriptional silencing mediated by RNAi and is a component of the RNAi pathway in Drosophila cultured cells (Dorner et al., 2006). The promoter region of the HSPa8 gene includes a TATA box, two CCAAT boxes, two SP1 elements and two sets of heat shock response elements (HSE) where the heat shock transcriptional factors bind (Chen et al., 2002).



The HSPA8 gene coding for the protein HSC70, also known as HSP73, is a 73 kDa heat shock cognate protein. HSC70 is an ATP binding chaperone and has intrinsic ATPase activity which hydrolyzes ATP into ADP (Jakob et al., 1996). HSC70 hydrolyzing ATP initiates the conformational change of HSC70 and further causes substrate binding by HSC70 (Sullivan and Pipas, 2002).
Atlas Image
The model for HSC70 and substrates binding and releasing cycle. In the ATP-bound state, HSC70 has low affinity with the substrates. After hydrolysis of ATP with the ATPase activity, HSC70 in the ADP bound state binds with the substrates with high affinity. Some co-chaperones such as Dna J homologues enhance the ATPase activity of HSC70. Nucleotide exchange factors such as GrpE enhance the dissociation of bound ADP from HSC70 to allow the binding of ATP, resetting the cycle.


HSC70, also called HSP73, is a 73 kDa heat shock cognate protein. The basic structure of human HSC70 includes three parts: a 44 kDa amino-terminal adenosine triphosphatase (ATPase) domain (residues 1-384), also known as the ATP-binding domain, an 18 kDa peptide (substrate) binding domain (residues 385-543), and a 10 kDa carboxyl-terminal domain (residues 544-646) which is also designated as the variable or "lid" domain (Smith et al., 1998; Tsukahara et al., 2000; Sullivan and Pipas, 2002). The carboxyl-terminal amino acid sequence Glu-Glu-Val-Asp (EEVD motif), which is absolutely conserved in all eukaryotic HSC70 and HSP70 family members, is essential for association with some co-chaperones (Mosser et al., 2000). Two amino acid sequences have the characteristics of nuclear localization signals in human HSC70 which are involved in nuclear import of HSC70: DAKRL69-73 in the amino-terminal and KRKHKKDISENKRAVRR246-262 in the ATPase domain (Lamian et al., 1996; Tsukahara and Maru, 2004).
Atlas Image
The structure of HSC70. The basic structure of human HSC70 includes three parts: a 44 kDa ATPase domain, an 18 kDa peptide (substrate) binding domain and a 10 kDa carboxyl-terminal domain, also known as "lid" domain.


Various conditions and molecules can affect the expression of the HSPA8 gene. The table below summarizes the factors which affect the expression of the HSPA8 gene (Liu et al., 2012).
Atlas Image


HSC70 is a major cytosolic molecular chaperone (Place and Hofmann, 2005). However, HSC70 is also located in various cellular locations such as nuclear and close to cellular membrane (Arispe et al., 2002). HSC70 can interact with the lipid bilayer in the cellular membrane directly and form ion-conductance channels allowing ion flow through the cellular membrane. HSC70 is also identified as a tyrosine-phosphorylated protein associated with the nuclear envelope. HSC70 supports the nuclear import of karyophilic proteins and may play a role in nucleocytoplasmic transport (Otto et al., 2001).


1. As a molecular chaperone, HSC70 regulates protein folding, maintains protein normal structure and functions, and protects cells from physical and chemcial damage. HSC70 regulates protein maturation and interacts with nascent polypeptides in the process of new protein synthesis (Beckmann et al., 1990; Beckmann et al.,1992). HSC70 can also regulate the translocation of proteins into different cellular organelles such as endoplasmic reticulum and mitochondria (Chirico et al., 1998, Sheffield et al., 1990).
2. HSC70 was oginally characterized as an uncoating ATPase that dissociates clathrin triskelions from clathrin-coated vesicles. It catalyzes the ATP-dependent uncoating of clathrin-coated pits (chappell et al., 1986; Goldfarb et al., 2005).
3. HSC70 is involved in targeting protein to lysosomes for degradation (Terlecky et al., 1992) and to ubiquitin/proteasome machinery for degradation (Massyuki, 1994).
4. HSC70 regulates cellular signaling and functions such as steroid receptor maturation and Akt signaling pathway (Kimmins and MacRae, 2000; Shiota et al., 2010).
5. HSC70 is important in regulating apoptosis, embryonic development and aging (Beere, 2004; Sreedhar and Csermely, 2004; Kodiha et al., 2005).


HSC70 belongs to the HSP70 family in which includes other three members: the HSP70, the glucose-regulated protein 78 (GRP78), and HSP75. Human HSC70 shares 85% amino acid similarity with HSP70 (Ali et al., 2003). They have similar functions and interact with each other in an ATP-dependent manner. HSC70 can form a stable complex with newly synthesized HSP70 upon heat shock (Brown et al., 1993).

Implicated in

Entity name
Various cancers
The HSPA8 gene is higher expressed in some cancer cells such as human colon cancer (Kubota et al., 2000).
HSC70 regulates functions of various cancer-related genes and proteins. HSC70 functions as a molecular stabilizer of nonphosphorylated retinoblastoma protein (pRb) by directly binding to it (Inoue et al., 1995). HSC70 binds to a mutant form of p53 and p73 and links them for degradation. HSPA8 gene can suppress oncogene (such as mutant p53 and Ras) mediated transformation (Yehiely and Oren, 1992; Gaiddon et al., 2001).
Intronic polymorphism (1541-1542delGT) of HSPA8 is associated with decrease of lung cancer risk (Rusin et al., 2004).
Entity name
Cadiovascular diseases
HSC70 plays a protective role in myocardial injuries. HSC70 is commonly found in atherosclerotic plaques during the atherogenesis and therosclerotic plaque progression and it appears to be a protective factor against cellular stress (Dupont et al., 2008). HSC70 expression is significantly decreased in diabetic myocardium because of insulin deficiency. Insulin directly increases the abundance of HSC70 in cultured cardiomyocytes and overexpression of HSC70 leads to protect against stress via suppression of apoptosis signalling (Chen et al., 2006).
Entity name
Neurological diseases
HSC70 is directly involved in cell survival during neurulation and HSC70 acts as an intrinsic protector of neuroepithelial and neural precursor cells (Rubio et al., 2002). HSC70 mediates the chaperone mediated lysosomal degradation of α-synuclei which is accumulated in Parkingsons disease and other neurodegenerative diseases (Mak et al., 2010). HSC70 facilitates degradation of the amyotrophic lateral sclerosis (ALS) -linked mutant SOD1 protein in an ubiquitination-dependent manner (Urushitani et al., 2004; Casoni et al., 2005). HSC70 mediates the autophagy for the degradation of mutant huntingtin protein which can cause Huntingtons disease (Bauer et al., 2010).
Entity name
Liver diseases
HSC70 has been implicated in the pathogenesis and the pathophysiology of hepatic diseases such as hepatitis B and C, non-alcoholic steatohepatitis autoimmune hepatitis, and primary biliary cirrhosis. HSC70 plays important role in the replication of hepatitis B virus and hepatitis C virus. HSC70 could be a novel molecular target for diagnosis and treatment of hepatitis B and C (Wang et al., 2010).


Pubmed IDLast YearTitleAuthors
128932502003Tissue- and stressor-specific differential expression of two hsc70 genes in carp.Ali KS et al
108991682000ATP and ADP modulate a cation channel formed by Hsc70 in acidic phospholipid membranes.Arispe N et al
201907392010Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein.Bauer PO et al
16073781992Examining the function and regulation of hsp 70 in cells subjected to metabolic stress.Beckmann RP et al
151698352004"The stress of dying": the role of heat shock proteins in the regulation of apoptosis.Beere HM et al
84365861993The constitutive and stress inducible forms of hsp 70 exhibit functional similarities and interact with one another in an ATP-dependent fashion.Brown CR et al
156990432005Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis.Casoni F et al
29375421986Uncoating ATPase is a member of the 70 kilodalton family of stress proteins.Chappell TG et al
168995762006Downregulation of the constitutively expressed Hsc70 in diabetic myocardium is mediated by insulin deficiency.Chen HS et al
92225891996Amplification and altered expression of the hsc70/U14 snoRNA gene in a heat resistant Chinese hamster cell line.Chen MS et al
118929892002Differential accumulation of U14 snoRNA and hsc70 mRNA in Chinese hamster cells after exposure to various stress conditions.Chen MS et al
3282179198870K heat shock related proteins stimulate protein translocation into microsomes.Chirico WJ et al
125889942003Hsc70 regulates accumulation of cyclin D1 and cyclin D1-dependent protein kinase.Diehl JA et al
168827162006A genomewide screen for components of the RNAi pathway in Drosophila cultured cells.Dorner S et al
185492652008Application of saturation dye 2D-DIGE proteomics to characterize proteins modulated by oxidized low density lipoprotein treatment of human macrophages.Dupont A et al
30374891987Structure and expression of a human gene coding for a 71 kd heat shock 'cognate' protein.Dworniczak B et al
168955832006Region-specific regulation of glucocorticoid receptor/HSP90 expression and interaction in brain.Furay AR et al
112389242001A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain.Gaiddon C et al
165855202006Differential effects of Hsc70 and Hsp70 on the intracellular trafficking and functional expression of epithelial sodium channels.Goldfarb SB et al
167853242006TOR coordinates bulk and targeted endocytosis in the Drosophila melanogaster fat body to regulate cell growth.Hennig KM et al
7673249199570-kDa heat shock cognate protein interacts directly with the N-terminal region of the retinoblastoma gene product pRb. Identification of a novel region of pRb-mediating protein interaction.Inoue A et al
86265581996Assessment of the ATP binding properties of Hsp90.Jakob U et al
111479682000Maturation of steroid receptors: an example of functional cooperation among molecular chaperones and their associated proteins.Kimmins S et al
159301402005Stress inhibits nucleocytoplasmic shuttling of heat shock protein hsc70.Kodiha M et al
206174062010Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma.Kubota H et al
88929741996Evidence for the existence of a novel mechanism for the nuclear import of Hsc70.Lamian V et al
229603942012Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential.Liu T et al
202001632010Lysosomal degradation of alpha-synuclein in vivo.Mak SK et al
109828312000The chaperone function of hsp70 is required for protection against stress-induced apoptosis.Mosser DD et al
80827771994A 70-kDa heat shock cognate protein suppresses the defects caused by a proteasome mutation in Saccharomyces cerevisiae.Ohba M et al
111683782001Identification of tyrosine-phosphorylated proteins associated with the nuclear envelope.Otto H et al
156371652005Comparison of Hsc70 orthologs from polar and temperate notothenioid fishes: differences in prevention of aggregation and refolding of denatured proteins.Place SP et al
120599722002Programmed cell death in the neurulating embryo is prevented by the chaperone heat shock cognate 70.Rubio E et al
149917452004Intronic polymorphism (1541-1542delGT) of the constitutive heat shock protein 70 gene has functional significance and shows evidence of association with lung cancer risk.Rusin M et al
21930311990Mitochondrial precursor protein. Effects of 70-kilodalton heat shock protein on polypeptide folding, aggregation, and import competence.Sheffield WP et al
200189372010Heat shock cognate protein 70 is essential for Akt signaling in endothelial function.Shiota M et al
98608031998Molecular chaperones: biology and prospects for pharmacological intervention.Smith DF et al
118960432002Invited review: Effects of heat and cold stress on mammalian gene expression.Sonna LA et al
150310012004Heat shock proteins in the regulation of apoptosis: new strategies in tumor therapy: a comprehensive review.Sreedhar AS et al
120401232002T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis.Sullivan CS et al
15777551992Protein and peptide binding and stimulation of in vitro lysosomal proteolysis by the 73-kDa heat shock cognate protein.Terlecky SR et al
146847482004Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70.Tsukahara F et al
151986822004CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70.Urushitani M et al
201768932010Heat stress cognate 70 host protein as a potential drug target against drug resistance in hepatitis B virus.Wang YP et al
14673071992The gene for the rat heat-shock cognate, hsc70, can suppress oncogene-mediated transformation.Yehiely F et al
165807372006Fusion protein of ATPase domain of Hsc70 with TRP2 acting as a tumor vaccine against B16 melanoma.Zhang H et al

Other Information

Locus ID:

NCBI: 3312
MIM: 600816
HGNC: 5241
Ensembl: ENSG00000109971


dbSNP: 3312
ClinVar: 3312
TCGA: ENSG00000109971


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Antigen processing and presentationKEGGko04612
MAPK signaling pathwayKEGGhsa04010
Antigen processing and presentationKEGGhsa04612
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Spliceosome, Prp19/CDC5L complexKEGGhsa_M00353
Spliceosome, 35S U5-snRNPKEGGhsa_M00355
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
Spliceosome, Prp19/CDC5L complexKEGGM00353
Spliceosome, 35S U5-snRNPKEGGM00355
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Release CycleREACTOMER-HSA-112310
GABA synthesis, release, reuptake and degradationREACTOMER-HSA-888590
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Gene ExpressionREACTOMER-HSA-74160
Processing of Capped Intron-Containing Pre-mRNAREACTOMER-HSA-72203
mRNA SplicingREACTOMER-HSA-72172
mRNA Splicing - Major PathwayREACTOMER-HSA-72163
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
AUF1 (hnRNP D0) binds and destabilizes mRNAREACTOMER-HSA-450408
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
trans-Golgi Network Vesicle BuddingREACTOMER-HSA-199992
Clathrin derived vesicle buddingREACTOMER-HSA-421837
Golgi Associated Vesicle BiogenesisREACTOMER-HSA-432722
Lysosome Vesicle BiogenesisREACTOMER-HSA-432720
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
L1CAM interactionsREACTOMER-HSA-373760
CHL1 interactionsREACTOMER-HSA-447041
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
HSF1-dependent transactivationREACTOMER-HSA-3371571
Attenuation phaseREACTOMER-HSA-3371568
Regulation of HSF1-mediated heat shock responseREACTOMER-HSA-3371453
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
Clathrin-mediated endocytosisREACTOMER-HSA-8856828
Neutrophil degranulationREACTOMER-HSA-6798695
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Protein methylationREACTOMER-HSA-8876725

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
187721142008Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis.136
146124562004CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival.133
157952422005Heat shock protein 90 and heat shock protein 70 are components of dengue virus receptor complex in human cells.110
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
233496342013A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.71
151947942004Nuclear sequestration of cellular chaperone and proteasomal machinery during herpes simplex virus type 1 infection.59
211482932011The endoplasmic reticulum-associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3-dependent degradation of nascent CFTRDeltaF508.55
235692232013Regulation of Torsin ATPases by LAP1 and LULL1.54
238806652013STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy.54
272611982016DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins.50


Tuoen Liu ; Shousong Cao

HSPA8 (heat shock 70kDa protein 8)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/40878/hspa8