View source for Hsp70

{{short description|Family of heat shock proteins}}
{{Infobox protein family
| Symbol = HSP70
| Name = Hsp70 protein
| image = PDB 3hsc EBI.jpg
| width =
| caption = Structure of the ATPase fragment of a 70K heat-shock cognate protein.<ref name="pmid2143562">{{cite journal | vauthors = Flaherty KM, DeLuca-Flaherty C, McKay DB | title = Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein | journal = Nature | volume = 346 | issue = 6285 | pages = 623–8 | date = August 1990 | pmid = 2143562 | doi = 10.1038/346623a0 | bibcode = 1990Natur.346..623F | s2cid = 4338916 }}</ref>
| Pfam= PF00012
| Pfam_clan = CL0108
| InterPro=IPR013126
| SMART=
| PROSITE =PDOC00269
| SCOP = 3hsc
| TCDB =
}}
[[File:HSP70 in pathologies.png|thumb|'''Schematic diagram highlighting the role of HSP70 in pathologies. The protective intracellular HSP70 is decreased whereas the levels of inflammatory extracellular HSP70 is increased. This imbalance leads to disease progression.''']]
The '''70 kilodalton heat shock proteins''' ('''Hsp70'''s or '''DnaK''') are a [[protein family|family]] of [[sequence conservation|conserved]] ubiquitously expressed [[heat shock protein]]s. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for [[protein folding]], performing chaperoning functions, and helping to protect cells from the adverse effects of [[physiological stress]]es.<ref name="pmid9222585">{{cite journal | vauthors = Tavaria M, Gabriele T, Kola I, Anderson RL | title = A hitchhiker's guide to the human Hsp70 family | journal = Cell Stress & Chaperones | volume = 1 | issue = 1 | pages = 23–8 | date = April 1996 | doi = 10.1379/1466-1268(1996)001<0023:ahsgtt>2.3.co;2 | doi-broken-date = 1 November 2024 | pmid = 9222585 | pmc = 313013 }}</ref><ref name="pmid17513460">{{cite journal | vauthors = Morano KA | title = New tricks for an old dog: the evolving world of Hsp70 | journal = Annals of the New York Academy of Sciences | volume = 1113 | issue = 1 | pages = 1–14 | date = October 2007 | pmid = 17513460 | doi = 10.1196/annals.1391.018 | bibcode = 2007NYASA1113....1M | s2cid = 20917046 }}</ref> Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies<ref name="GiriSethi2017">{{cite journal | vauthors = Giri B, Sethi V, Modi S, Garg B, Banerjee S, Saluja A, Dudeja V | title = "Heat shock protein 70 in pancreatic diseases: Friend or foe" | journal = Journal of Surgical Oncology | volume = 116 | issue = 1 | pages = 114–122 | date = July 2017 | pmid = 28543919 | doi = 10.1002/jso.24653 | pmc = 5714583 }}</ref> and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.<ref name="De Maio2014">{{cite journal | vauthors = De Maio A | title = Extracellular Hsp70: export and function | journal = Current Protein & Peptide Science | volume = 15 | issue = 3 | pages = 225–31 | date = May 2014 | pmid = 24694368 | doi = 10.2174/1389203715666140331113057 }}</ref>
== Discovery ==
Members of the Hsp70 family are very strongly upregulated by heat stress and [[toxic]] chemicals, particularly heavy metals such as arsenic, cadmium, copper, mercury, etc. Heat shock was originally discovered by [[Ferruccio Ritossa]] in the 1960s when a lab worker accidentally boosted the incubation temperature of [[Drosophila]] (fruit flies). When examining the chromosomes, Ritossa found a "puffing pattern" that indicated the elevated gene transcription of an unknown protein.<ref name="Ritossa_1962">{{cite journal | vauthors = Ritossa F | title = A new puffing pattern induced by temperature shock and DNP in drosophila | journal = Cellular and Molecular Life Sciences | volume = 18 | issue = 12 | pages = 571–573 | year = 1962 | doi = 10.1007/BF02172188 | s2cid = 32525462 }}</ref><ref name="pmid9222594">{{cite journal | vauthors = Ritossa F | title = Discovery of the heat shock response | journal = Cell Stress & Chaperones | volume = 1 | issue = 2 | pages = 97–8 | date = June 1996 | doi = 10.1379/1466-1268(1996)001<0097:dothsr>2.3.co;2 | doi-broken-date = 1 November 2024 | pmid = 9222594 | pmc = 248460 }}</ref> This was later described as the "Heat Shock Response" and the proteins were termed the "Heat Shock Proteins" (Hsps).
== Structure ==
[[File:Figure- Hsp70 family schematic domains and Secondary structures of Hsp70 family.jpg|thumb|360px|(a) The Hsp70s schematic domains. The Hsp70s consist of two high conserved functional domains including an NBD and a C‐terminal substrate‐binding domain (SBD), also an EEVD‐motif at C‐terminal. The NBD contains the ATP/ADP pocket that binds and The SBD contains a substrate‐binding pocket that interacts with extended polypeptides as substrate, an α‐helical subdomain from the C‐terminal side of SBD forms a flexible lid. EEVD‐motif participates in binding to co‐chaperones and other HSPs. (b) the complete amino acid sequence of human Hsp70 (UniProtKB identifier: P0DMV8) as a major stress‐inducible member of the Hsp70 family. (c) Secondary structures of Hsp70 virtualized using VMD 1.9.1 software. Hsp70, heat shock protein 70 kDa; NBD, N‐terminal nucleotide‐binding domain; SBD, substrate binding domain at C‐terminal.<ref name="pmid33169384"/>
]]
The Hsp70 proteins have three major functional [[protein domain|domains]]:
* '''[[N-terminus|N-terminal]] [[ATPase]] domain''' – binds ATP ([[Adenosine triphosphate]]) and hydrolyzes it to ADP ([[Adenosine diphosphate]]). The NBD (nucleotide binding domain) consists of two lobes with a deep cleft between them, at the bottom of which nucleotide (ATP and ADP) binds. The exchange of ATP and ADP leads to conformational changes in the other two domains.
* '''Substrate binding domain''' – is composed of a 15 [[kDa]] β sheet subdomain and a 10 kDa helical subdomain. The β sheet subdomain consists of stranded β sheets with upward protruding loops, as a typical [[β barrel]], which enclose the peptide backbone of the substrate. SBD contains a groove with an affinity for neutral, hydrophobic [[amino acid]] residues. The groove is long enough to interact with peptides up to seven residues in length.
* '''[[C-terminus|C-terminal]] domain''' – rich in [[alpha helix|alpha helical structure]] acts as a 'lid' for the substrate binding domain. The helical subdomain consists of five helices, with two helices packed against two sides of the β sheet subdomain, stabilizing the inner structure. In addition, one of the helix forms a salt bridge and several hydrogen bonds to the outer Loops, thereby closing the substrate-binding pocket like a lid. Three helices in this domain form another hydrophobic core which may be stabilization of the "lid". When an Hsp70 protein is ATP bound, the lid is open and peptides bind and release relatively rapidly. When Hsp70 proteins are ADP bound, the lid is closed, and peptides are tightly bound to the substrate binding domain.<ref name="Mayer_2010">{{cite journal | vauthors = Mayer MP | title = Gymnastics of molecular chaperones | journal = Molecular Cell | volume = 39 | issue = 3 | pages = 321–31 | date = August 2010 | pmid = 20705236 | doi = 10.1016/j.molcel.2010.07.012 | doi-access = free }}</ref>
[[File:Serine Phosphorylation.png|thumb|Phosphorylation of isolated serine residue by protein kinase.]]
Protein phosphorylation, a post-translational modification, helps to regulate protein function and involves the phosphorylation of amino acids with hydroxyl groups in their side chains (among eukaryotes). Serine, threonine, and tyrosine amino acids are common targets of phosphorylation. Phosphorylation of Hsp70 has become a point of greater exploration in scientific literature relatively recently. A 2020 publication suggests that phosphorylation of a serine residue between the NBD and substrate binding domain in yeast Hsp70s leads to a dramatic reduction of the normal Hsp70 heat shock response.<ref name="KaoRyu2020">{{cite journal | vauthors = Kao CH, Ryu SW, Kim MJ, Wen X, Wimalarathne O, Paull TT | title = Growth-Regulated Hsp70 Phosphorylation Regulates Stress Responses and Prion Maintenance | journal = Molecular and Cellular Biology | volume = 40 | issue = 12 | date = May 2020 | pmid = 32205407 | doi = 10.1128/MCB.00628-19 | pmc = 7261718 }}</ref> This deactivation via phosphorylation of a protein is a common motif in protein regulation, and demonstrates how relatively small changes to protein structure can have biologically significant effects on protein function.
== Function ==
The Hsp70 system interacts with extended peptide segments of proteins as well as partially folded proteins to cause aggregation of proteins in key pathways to downregulate activity.<ref name="pmid27783598">{{cite journal | vauthors = Mashaghi A, Bezrukavnikov S, Minde DP, Wentink AS, Kityk R, Zachmann-Brand B, Mayer MP, Kramer G, Bukau B, Tans SJ | display-authors = 6 | title = Alternative modes of client binding enable functional plasticity of Hsp70 | journal = Nature | volume = 539 | issue = 7629 | pages = 448–451 | date = November 2016 | pmid = 27783598 | doi = 10.1038/nature20137 | bibcode = 2016Natur.539..448M | s2cid = 4401991 }}</ref><ref name="pmid33169384">{{cite journal | vauthors = Vostakolaei MA, Hatami-Baroogh L, Babaei G, Molavi O, Kordi S, Abdolalizadeh J | title = Hsp70 in cancer: A double agent in the battle between survival and death | journal = Journal of Cellular Physiology | volume = 236 | issue = 5 | pages = 3420–3444 | date = May 2021 | pmid = 33169384 | doi = 10.1002/jcp.30132 | s2cid = 226295557 }}</ref> When not interacting with a substrate peptide, Hsp70 is usually in an ATP bound state. Hsp70 by itself is characterized by a very weak [[ATPase]] activity, such that spontaneous hydrolysis will not occur for many minutes. As newly synthesized proteins emerge from the [[ribosome]]s, the substrate binding domain of Hsp70 recognizes sequences of hydrophobic [[amino acid residue]]s, and interacts with them. This spontaneous interaction is reversible, and in the ATP bound state Hsp70 may relatively freely bind and release [[peptide]]s. However, the presence of a peptide in the binding domain stimulates the ATPase activity of Hsp70, increasing its normally slow rate of ATP hydrolysis. When ATP is hydrolyzed to ADP the binding pocket of Hsp70 closes, tightly binding the now-trapped peptide chain. Further speeding [[ATP hydrolysis]] are the so-called J-domain cochaperones: primarily [[Hsp40]] in [[eukaryotes]], and DnaJ in [[prokaryotes]]. These cochaperones dramatically increase the ATPase activity of Hsp70 in the presence of interacting peptides.
[[File:Figure Hsp70 function cycle.jpg|The function of Hsp70 in both (re) folding and degradation of misfolded client protein. (a) Schematic of the Hsp70 ATP–ADP cycle for (re) folding of client protein which causes a conformational change of the chaperone, ATP hydrolysis, and exchange. (b) Hsp70–CHIP complex that promotes client protein ubiquitination and proteasomal degradation. CHIP interacts with the TPR domain of Hsp70 and acts as a ubiquitin ligase for clients. CHIP, chromatin immunoprecipitation; Hsp70, heat shock protein 70 kDa; TPR, tetratricopeptide‐repeat domain<ref name="pmid33169384"/>|thumb|433x433px]]
By binding tightly to partially synthesized peptide sequences (incomplete proteins), Hsp70 prevents them from aggregating and being rendered nonfunctional. Once the entire protein is synthesized, a [[nucleotide exchange factor]] (prokaryotic [[GrpE]], eukaryotic [[BAG1]] and [[HSPBP1|HspBP1]] are among those which have been identified) stimulates the release of ADP and binding of fresh ATP, opening the binding pocket. The protein is then free to fold on its own, or to be transferred to other chaperones for further processing.<ref name="pmid25487014">{{cite book | vauthors = Bracher A, Verghese J | chapter = GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG Domain Proteins: Nucleotide Exchange Factors for Hsp70 Molecular Chaperones | title = The Networking of Chaperones by Co-chaperones | volume = 78 | pages = 1–33 | date = 2015 | pmid = 25487014 | doi = 10.1007/978-3-319-11731-7_1 | isbn = 978-3-319-11730-0 | series = Subcellular Biochemistry }}</ref> [[Hop (protein)|HOP]] (the '''H'''sp70/Hsp90 '''O'''rganizing '''P'''rotein) can bind to both Hsp70 and Hsp90 at the same time, and mediates the transfer of peptides from Hsp70 to Hsp90.<ref name="pmid14740253">{{cite book |vauthors=Wegele H, Müller L, Buchner J | title = Hsp70 and Hsp90 – a relay team for protein folding | chapter = Hsp70 and Hsp90—a relay team for protein folding | journal = Rev. Physiol. Biochem. Pharmacol. | volume = 151 | pages = 1–44 | year = 2004 | pmid = 14740253 | doi = 10.1007/s10254-003-0021-1 | series = Reviews of Physiology, Biochemistry and Pharmacology | isbn = 978-3-540-22096-1 }}</ref>
Hsp70 also aids in transmembrane transport of proteins, by stabilizing them in a partially folded state. It is also known to be phosphorylated<ref>{{cite journal | vauthors = Cvoro A, Dundjerski J, Trajković D, Matić G | title = The level and phosphorylation of Hsp70 in the rat liver cytosol after adrenalectomy and hyperthermia | journal = Cell Biology International | volume = 23 | issue = 4 | pages = 313–20 | date = 1999-04-01 | pmid = 10600240 | doi = 10.1006/cbir.1998.0247 | s2cid = 9113738 }}</ref> which regulates several of its functions.<ref>{{cite journal | vauthors = Gao T, Newton AC | title = The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C | journal = The Journal of Biological Chemistry | volume = 277 | issue = 35 | pages = 31585–92 | date = August 2002 | pmid = 12080070 | doi = 10.1074/jbc.M204335200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Truman AW, Kristjansdottir K, Wolfgeher D, Hasin N, Polier S, Zhang H, Perrett S, Prodromou C, Jones GW, Kron SJ | display-authors = 6 | title = CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression | journal = Cell | volume = 151 | issue = 6 | pages = 1308–18 | date = December 2012 | pmid = 23217712 | pmc = 3778871 | doi = 10.1016/j.cell.2012.10.051 }}</ref><ref>{{cite journal | vauthors = Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP, Vojtesek B | title = C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances | journal = Oncogene | volume = 32 | issue = 25 | pages = 3101–10 | date = June 2013 | pmid = 22824801 | doi = 10.1038/onc.2012.314 | s2cid = 12604151 | doi-access = free }}</ref>
Hsp70 proteins can act to protect cells from thermal or oxidative stress. These stresses normally act to damage proteins, causing partial unfolding and possible aggregation. By temporarily binding to hydrophobic residues exposed by stress, Hsp70 prevents these partially denatured proteins from aggregating, and inhibits them from refolding. Low ATP is characteristic of heat shock and sustained binding is seen as aggregation suppression, while recovery from heat shock involves substrate binding and nucleotide cycling. In a thermophile anaerobe (''Thermotoga maritima'') the Hsp70 demonstrates redox sensitive binding to model peptides, suggesting a second mode of binding regulation based on oxidative stress.
Hsp70 seems to be able to participate in disposal of damaged or defective proteins. Interaction with [[STUB1|CHIP]] (''C''arboxyl-terminus of ''H''sp70 ''I''nteracting ''P''rotein)–an E3 [[ubiquitin ligase]]–allows Hsp70 to pass proteins to the cell's [[ubiquitin]]ation and [[proteasome|proteolysis]] pathways.<ref name="pmid10671488">{{cite journal | vauthors = Lüders J, Demand J, Höhfeld J | title = The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome | journal = The Journal of Biological Chemistry | volume = 275 | issue = 7 | pages = 4613–7 | date = February 2000 | pmid = 10671488 | doi = 10.1074/jbc.275.7.4613 | doi-access = free }}</ref>
Finally, in addition to improving overall protein integrity, Hsp70 directly inhibits [[apoptosis]].<ref name="pmid10934466">{{cite journal | vauthors = Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR | display-authors = 6 | title = Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome | journal = Nature Cell Biology | volume = 2 | issue = 8 | pages = 469–75 | date = August 2000 | pmid = 10934466 | doi = 10.1038/35019501 | s2cid = 1507966 }}</ref> One hallmark of apoptosis is the release of [[cytochrome c]], which then recruits Apaf-1 and dATP/ATP into an [[apoptosome]] complex. This complex then cleaves procaspase-9, activating caspase-9 and eventually inducing apoptosis via [[caspase 3]] activation. Hsp70 inhibits this process by blocking the recruitment of procaspase-9 to the Apaf-1/dATP/cytochrome c apoptosome complex. It does not bind directly to the procaspase-9 binding site, but likely induces a conformational change that renders procaspase-9 binding less favorable. Hsp70 is shown to interact with [[Endoplasmic reticulum]] stress sensor protein IRE1alpha thereby protecting the cells from ER stress - induced apoptosis. This interaction prolonged the splicing of XBP-1 mRNA thereby inducing transcriptional upregulation of targets of spliced XBP-1 like EDEM1, ERdj4 and P58IPK rescuing the cells from apoptosis.<ref name="pmid20625543">{{cite journal | vauthors = Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C, Samali A | title = HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction | journal = PLOS Biology | volume = 8 | issue = 7 | pages = e1000410 | date = July 2010 | pmid = 20625543 | pmc = 2897763 | doi = 10.1371/journal.pbio.1000410 | veditors = Kelly JW | doi-access = free }}</ref> Other studies suggest that Hsp70 may play an anti-apoptotic role at other steps, but is not involved in Fas-ligand-mediated apoptosis (although Hsp 27 is). Therefore, Hsp70 not only saves important components of the cell (the proteins) but also directly saves the cell as a whole. Considering that stress-response proteins (like Hsp70) evolved before apoptotic machinery, Hsp70's direct role in inhibiting apoptosis provides an interesting evolutionary picture of how more recent (apoptotic) machinery accommodated previous machinery (Hsps), thus aligning the improved integrity of a cell's proteins with the improved chances of that particular cell's survival.
In mice, exogenous recombinant human Hsp70 (eHsp70), delivered [[Nasal administration|intranasally]], increases lifespan. Although the maximum lifespan increased only moderately, the overall mortality rate in treated animals was much lower compared with the control group. Also this eHsp70-treatment improves learning and memory of mice in old age, increases their curiosity.<ref>{{cite journal | vauthors = Bobkova NV, Evgen'ev M, Garbuz DG, Kulikov AM, Morozov A, Samokhin A, Velmeshev D, Medvinskaya N, Nesterova I, Pollock A, Nudler E | display-authors = 6 | title = Exogenous Hsp70 delays senescence and improves cognitive function in aging mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 52 | pages = 16006–16011 | date = December 2015 | pmid = 26668376 | pmc = 4702952 | doi = 10.1073/pnas.1516131112 | bibcode = 2015PNAS..11216006B | doi-access = free }}</ref>
== Cancer ==
Hsp70 is overexpressed in [[malignant melanoma]]<ref name="pmid11237497">{{cite journal | vauthors = Ricaniadis N, Kataki A, Agnantis N, Androulakis G, Karakousis CP | title = Long-term prognostic significance of HSP-70, c-myc and HLA-DR expression in patients with malignant melanoma | journal = European Journal of Surgical Oncology | volume = 27 | issue = 1 | pages = 88–93 | date = February 2001 | pmid = 11237497 | doi = 10.1053/ejso.1999.1018 }}</ref> and underexpressed in [[renal cell cancer]].<ref name="pmid17616937">{{cite journal | vauthors = Ramp U, Mahotka C, Heikaus S, Shibata T, Grimm MO, Willers R, Gabbert HE | title = Expression of heat shock protein 70 in renal cell carcinoma and its relation to tumor progression and prognosis | journal = Histology and Histopathology | volume = 22 | issue = 10 | pages = 1099–107 | date = October 2007 | pmid = 17616937 | doi = 10.14670/HH-22.1099 }}</ref><ref name="urlHSP">{{cite journal | vauthors = Sherman M, Multhoff G | title = Heat shock proteins in cancer | journal = Annals of the New York Academy of Sciences | volume = 1113 | issue = 1 | pages = 192–201 | date = October 2007 | pmid = 17978282 | doi = 10.1196/annals.1391.030 | bibcode = 2007NYASA1113..192S | s2cid = 39372827 }}</ref>
In [[breast cancer]] cell line (MCF7) has been found that not only Hsp90 interacted with [[estrogen receptor alpha]] (ERα) but also Hsp70-1 and [[Hsc70]] interacted with ERα too.<ref>{{cite journal | vauthors = Dhamad AE, Zhou Z, Zhou J, Du Y | title = Systematic Proteomic Identification of the Heat Shock Proteins (Hsp) that Interact with Estrogen Receptor Alpha (ERα) and Biochemical Characterization of the ERα-Hsp70 Interaction | journal = PLOS ONE | volume = 11 | issue = 8 | pages = e0160312 | date = 2016 | pmid = 27483141 | doi = 10.1371/journal.pone.0160312 | pmc = 4970746 | bibcode = 2016PLoSO..1160312D | doi-access = free }}</ref>
Given the role of heat shock proteins as an ancient defense system for stabilizing cells and eliminating old and damaged cells, this system has been co-opted by cancer cells to promote their growth.<ref name="MartinkováTrčka 2018">{{cite journal | vauthors = Martinková V, Trčka F, Vojtěšek B, Müller P | title = The Role of HSP70 in Cancer and its Exploitation as a Therapeutic Target | journal = Klinicka Onkologie | volume = 31 | issue = Suppl 2 | pages = 46–54 | year = 2018 | pmid = 31023024 | doi = 10.14735/amko20182S46 | doi-access = free }}</ref> Increased Hsp70 in particular has been shown to inhibit apoptosis of cancer cells,<ref name="Moradi‐MarjanehPaseban2019">{{cite journal | vauthors = Moradi-Marjaneh R, Paseban M, Moradi Marjaneh M | title = Hsp70 inhibitors: Implications for the treatment of colorectal cancer | journal = IUBMB Life | volume = 71 | issue = 12 | pages = 1834–1845 | date = December 2019 | pmid = 31441584 | doi = 10.1002/iub.2157 | s2cid = 201619393 | doi-access = free }}</ref> and increased Hsp70 has been shown to be associated with or directly induce endometrial,<ref name="DuJiang2009">{{cite journal | vauthors = Du XL, Jiang T, Wen ZQ, Gao R, Cui M, Wang F | title = Silencing of heat shock protein 70 expression enhances radiotherapy efficacy and inhibits cell invasion in endometrial cancer cell line | journal = Croatian Medical Journal | volume = 50 | issue = 2 | pages = 143–50 | date = April 2009 | pmid = 19399947 | doi = 10.3325/cmj.2009.50.143 | pmc = 2681060 }}</ref> lung,<ref name="GuntherOstheimer2015">{{cite journal | vauthors = Gunther S, Ostheimer C, Stangl S, Specht HM, Mozes P, Jesinghaus M, Vordermark D, Combs SE, Peltz F, Jung MP, Multhoff G | display-authors = 6 | title = Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer | journal = Frontiers in Immunology | volume = 6 | pages = 556 | year = 2015 | pmid = 26579130 | doi = 10.3389/fimmu.2015.00556 | pmc = 4629690 | doi-access = free }}</ref> colon,<ref name="D. BlackRezvani2016">{{cite journal | vauthors = Black JD, Rezvani K | title = Heat Shock Protein 70s as Potential Molecular Targets for Colon Cancer Therapeutics | journal = Current Medicinal Chemistry | volume = 23 | issue = 28 | pages = 3171–3188 | year = 2016 | pmid = 27356538 | doi = 10.2174/0929867323666160627105033 }}</ref> prostate,<ref name="MosesKim2018">{{cite journal | vauthors = Moses MA, Kim YS, Rivera-Marquez GM, Oshima N, Watson MJ, Beebe KE, Wells C, Lee S, Zuehlke AD, Shao H, Bingman WE, Kumar V, Malhotra SV, Weigel NL, Gestwicki JE, Trepel JB, Neckers LM | display-authors = 6 | title = Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer | journal = Cancer Research | volume = 78 | issue = 14 | pages = 4022–4035 | date = July 2018 | pmid = 29764864 | doi = 10.1158/0008-5472.CAN-17-3728 | pmc = 6050126 }}</ref> and breast<ref name="BarnesDix2001">{{cite journal | vauthors = Barnes JA, Dix DJ, Collins BW, Luft C, Allen JW | title = Expression of inducible Hsp70 enhances the proliferation of MCF-7 breast cancer cells and protects against the cytotoxic effects of hyperthermia | journal = Cell Stress & Chaperones | volume = 6 | issue = 4 | pages = 316–25 | date = October 2001 | doi = 10.1379/1466-1268(2001)006<0316:eoihet>2.0.co;2 | doi-broken-date = 1 November 2024 | pmid = 11795468 | pmc = 434414 }}</ref> cancer, as well as leukemia.<ref name="GuoZhang2019">{{cite journal | vauthors = Guo D, Zhang A, Huang J, Suo M, Zhong Y, Liang Y | title = Suppression of HSP70 inhibits the development of acute lymphoblastic leukemia via TAK1/Egr-1 | journal = Biomedicine & Pharmacotherapy | volume = 119 | pages = 109399 | date = November 2019 | pmid = 31521893 | doi = 10.1016/j.biopha.2019.109399 | s2cid = 202582093 | doi-access = free }}</ref> Hsp70 in cancer cells may be responsible for tumorigenesis and tumor progression by providing resistance to chemotherapy. Inhibition of Hsp70 has been shown to reduce the size of tumors and can cause their complete regression.<ref name="KumarStokes2016">{{cite journal | vauthors = Kumar S, Stokes J, Singh UP, Scissum Gunn K, Acharya A, Manne U, Mishra M | title = Targeting Hsp70: A possible therapy for cancer | journal = Cancer Letters | volume = 374 | issue = 1 | pages = 156–166 | date = April 2016 | pmid = 26898980 | doi = 10.1016/j.canlet.2016.01.056 | pmc = 5553548 }}</ref> Hsp70/Hsp90 is a particularly attractive target for therapeutics, because it is regulated by the inhibition of its ATPase activity, while other HSPs are regulated by nucleotides.<ref name="PowersJones2014">{{cite journal | vauthors = Powers MV, Jones K, Barillari C, Westwood I, van Montfort RL, Workman P | title = Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone? | journal = Cell Cycle | volume = 9 | issue = 8 | pages = 1542–50 | date = April 2010 | pmid = 20372081 | doi = 10.4161/cc.9.8.11204 | s2cid = 37329279 }}</ref> Several inhibitors have been designed for Hsp70 that are currently in clinical trials,<ref name="AlbakovaArmeev2020">{{cite journal | vauthors = Albakova Z, Armeev GA, Kanevskiy LM, Kovalenko EI, Sapozhnikov AM | title = HSP70 Multi-Functionality in Cancer | journal = Cells | volume = 9 | issue = 3 | pages = 587 | date = March 2020 | pmid = 32121660 | doi = 10.3390/cells9030587 | pmc = 7140411 | doi-access = free }}</ref> though as of now HSP90 inhibitors have been more successful.<ref name="MellatyarTalaei2018">{{cite journal | vauthors = Mellatyar H, Talaei S, Pilehvar-Soltanahmadi Y, Barzegar A, Akbarzadeh A, Shahabi A, Barekati-Mowahed M, Zarghami N | display-authors = 6 | title = Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art | journal = Biomedicine & Pharmacotherapy | volume = 102 | pages = 608–617 | date = June 2018 | pmid = 29602128 | doi = 10.1016/j.biopha.2018.03.102 | s2cid = 4505299 }}</ref> In addition, Hsp70 has been shown to be a regulator of the immune system, activating the immune system as an antigen.<ref name="KumarDeepak2009">{{cite journal | vauthors = Kumar S, Deepak P, Kumar S, Kishore D, Acharya A | title = Autologous Hsp70 induces antigen specific Th1 immune responses in a murine T-cell lymphoma | journal = Immunological Investigations | volume = 38 | issue = 6 | pages = 449–65 | year = 2009 | pmid = 19811405 | doi = 10.1080/08820130902802673 | s2cid = 24747281 }}</ref> Thus, tumor-derived Hsp70 has been suggested as a potential vaccine <ref name="GuzhovaMargulis2016">{{cite journal | vauthors = Guzhova IV, Margulis BA | title = HSP70-based anti-cancer immunotherapy | journal = Human Vaccines & Immunotherapeutics | volume = 12 | issue = 10 | pages = 2529–2535 | date = October 2016 | pmid = 27294301 | doi = 10.1080/21645515.2016.1190057 | pmc = 5084976 }}</ref> or avenue to target for immunotherapy.<ref name="KottkeSanchez-Perez2007">{{cite journal | vauthors = Kottke T, Sanchez-Perez L, Diaz RM, Thompson J, Chong H, Harrington K, Calderwood SK, Pulido J, Georgopoulos N, Selby P, Melcher A, Vile R | display-authors = 6 | title = Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer | journal = Cancer Research | volume = 67 | issue = 24 | pages = 11970–9 | date = December 2007 | pmid = 18089828 | doi = 10.1158/0008-5472.CAN-07-2259 | doi-access = free }}</ref> Given the increased expression of Hsp70 in cancer, it has been suggested as a biomarker for cancer prognostics, with high levels portending poor prognosis.<ref name="ChanteloupCordonnier2020">{{cite journal | vauthors = Chanteloup G, Cordonnier M, Isambert N, Bertaut A, Hervieu A, Hennequin A, Luu M, Zanetta S, Coudert B, Bengrine L, Desmoulins I, Favier L, Lagrange A, Pages PB, Gutierrez I, Lherminier J, Avoscan L, Jankowski C, Rébé C, Chevriaux A, Padeano MM, Coutant C, Ladoire S, Causeret S, Arnould L, Charon-Barra C, Cottet V, Blanc J, Binquet C, Bardou M, Garrido C, Gobbo J | display-authors = 6 | title = Monitoring HSP70 exosomes in cancer patients' follow up: a clinical prospective pilot study | journal = Journal of Extracellular Vesicles | volume = 9 | issue = 1 | pages = 1766192 | year = 2020 | pmid = 32595915 | doi = 10.1080/20013078.2020.1766192 | pmc = 7301715 }}</ref> An oncogenic mechanism illustrates how extracellular vesicles expressing HSP70 are produced by proliferative Acute Lymphoblastic Leukemia cells and can target and compromise a healthy hematopoiesis system during leukemia development.<ref name="Georgievski 2022">{{cite journal | vauthors = Georgievski A, Michel A, Thomas C, Mlamla Z, Pais de Barros JP, Lemaire-Ewing S, Garrido C, Quéré R | display-authors = 6 | title = Acute lymphoblastic leukemia-derived extracellular vesicles affect quiescence of hematopoietic stem and progenitor cells | journal = Cell Death Dis. | volume = 12 | issue = 4 | pages = 337| year = 2022 | pmid = 35414137 | doi = 10.1038/s41419-022-04761-5 | pmc = 9005650 | s2cid = 248127986 }}</ref>
== Expression in skin tissue ==
Both Hsp70 and [[HSP47]] were shown to be expressed in [[dermis]] and [[epidermis (skin)|epidermis]] following [[photorejuvenation|laser irradiation]], and the spatial and temporal changes in HSP expression patterns define the laser-induced thermal damage zone and the process of healing in tissues. Hsp70 may define biochemically the thermal damage zone in which cells are targeted for destruction, and HSP47 may illustrate the process of recovery from thermally induced damage.<ref name="Sajjadi_2013">{{cite journal | vauthors = Sajjadi AY, Mitra K, Grace M | title = Expression of heat shock proteins 70 and 47 in tissues following short-pulse laser irradiation: assessment of thermal damage and healing | journal = Medical Engineering & Physics | volume = 35 | issue = 10 | pages = 1406–14 | date = October 2013 | pmid = 23587755 | doi = 10.1016/j.medengphy.2013.03.011 | url = https://www.dropbox.com/s/zhkklbq9nrbzu03/MedEngPhy_2013.pdf }}</ref> HSP70 helps in protecting skin against the increased melanin and wrinkled formation induced due to UV exposure.<ref>{{cite journal | vauthors = Matsuda M, Hoshino T, Yamakawa N, Tahara K, Adachi H, Sobue G, Maji D, Ihn H, Mizushima T | display-authors = 6 | title = Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice | journal = The Journal of Investigative Dermatology | volume = 133 | issue = 4 | pages = 919–928 | date = April 2013 | pmid = 23096703 | doi = 10.1038/jid.2012.383 | doi-access = free }}</ref>
== Neurodegeneration ==
Inhibition of Hsp90 leads to Hsp70 and Hsp40 upregulation, which can channel misfolded protein for proteasome degradation, which can potentially inhibit the progression of neurodegenerative diseases.<ref name="LackieMaciejewski2017">{{cite journal | vauthors = Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, Prado VF, Prado MA | display-authors = 6 | title = The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases | journal = Frontiers in Neuroscience | volume = 11 | pages = 254 | year = 2017 | pmid = 28559789 | doi = 10.3389/fnins.2017.00254 | pmc = 5433227 | doi-access = free }}</ref> For example, Hsp70 overexpression in human neuroglioma cells transfected with mutant alpha-synuclein led to 50% less oligomeric alpha-synuclein species,<ref name="KoutsopoulosOuteiro2008">{{cite journal | vauthors = Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ | display-authors = 6 | title = Formation of toxic oligomeric alpha-synuclein species in living cells | journal = PLOS ONE | volume = 3 | issue = 4 | pages = e1867 | date = April 2008 | pmid = 18382657 | doi = 10.1371/journal.pone.0001867 | pmc = 2270899 | bibcode = 2008PLoSO...3.1867O | doi-access = free }}</ref> pointing towards the possibility that increasing its expression could diminish the spread of Parkinson's disease. Similarly, Hsp70 overexpression suppressed poly-Q dependent aggregation and neurodegeneration in cell cultures, yeast,<ref name="CarmichaelChatellier2000">{{cite journal | vauthors = Carmichael J, Chatellier J, Woolfson A, Milstein C, Fersht AR, Rubinsztein DC | title = Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 17 | pages = 9701–5 | date = August 2000 | pmid = 10920207 | doi = 10.1073/pnas.170280697 | pmc = 16928 | bibcode = 2000PNAS...97.9701C | doi-access = free }}</ref> fly,<ref name="WarrickChan1999">{{cite journal | vauthors = Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM | title = Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70 | journal = Nature Genetics | volume = 23 | issue = 4 | pages = 425–8 | date = December 1999 | pmid = 10581028 | doi = 10.1038/70532 | s2cid = 24632055 }}</ref> and mouse <ref name="WackerZareie2004">{{cite journal | vauthors = Wacker JL, Zareie MH, Fong H, Sarikaya M, Muchowski PJ | title = Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 12 | pages = 1215–22 | date = December 2004 | pmid = 15543156 | doi = 10.1038/nsmb860 | s2cid = 43035 }}</ref> models, and deletion of hsp70 increased the size of polyQ inclusion bodies,<ref name="WackerHuang2009">{{cite journal | vauthors = Wacker JL, Huang SY, Steele AD, Aron R, Lotz GP, Nguyen Q, Giorgini F, Roberson ED, Lindquist S, Masliah E, Muchowski PJ | display-authors = 6 | title = Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease | journal = The Journal of Neuroscience | volume = 29 | issue = 28 | pages = 9104–14 | date = July 2009 | pmid = 19605647 | doi = 10.1523/JNEUROSCI.2250-09.2009 | pmc = 2739279 }}</ref> suggesting that increasing its expression could help to prevent Huntington's disease. Similarly, reductions in Hsp70 have been shown in transgenic mouse models of ALS and patients with sporadic ALS.<ref name="ChenMitchell2016">{{cite journal | vauthors = Chen HJ, Mitchell JC, Novoselov S, Miller J, Nishimura AL, Scotter EL, Vance CA, Cheetham ME, Shaw CE | display-authors = 6 | title = The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis | journal = Brain | volume = 139 | issue = Pt 5 | pages = 1417–32 | date = May 2016 | pmid = 26936937 | doi = 10.1093/brain/aww028 | pmc = 4845254 }}</ref> Lastly, increased expression or activity of Hsp70 has been proposed as a method to prevent the progression of Alzheimer's disease, because knock down of Hsp70 promoted A-beta toxicity,<ref name="BrehmeVoisine2014">{{cite journal | vauthors = Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, Orton K, Villella A, Garza D, Vidal M, Ge H, Morimoto RI | display-authors = 6 | title = A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease | journal = Cell Reports | volume = 9 | issue = 3 | pages = 1135–50 | date = November 2014 | pmid = 25437566 | doi = 10.1016/j.celrep.2014.09.042 | pmc = 4255334 }}</ref> and Hsp70 was shown to promote tau stability, while Hsp70 levels are decreased in tauopathies like Alzheimer's disease.<ref name="DouNetzer2003">{{cite journal | vauthors = Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H | display-authors = 6 | title = Chaperones increase association of tau protein with microtubules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 2 | pages = 721–6 | date = January 2003 | pmid = 12522269 | doi = 10.1073/pnas.242720499 | pmc = 141063 | bibcode = 2003PNAS..100..721D | doi-access = free }}</ref> Given the complex interplay between the different chaperone proteins, therapeutic development in this field is aimed at investigating how the chaperone network as a whole can be manipulated and the effect of this manipulation on the progression of neurodegenerative disease, but the balance of Hsp70 and Hsp90 levels appears to be central in this pathophysiology.
== In diabetes ==
The fluctuations in the levels of chaperone HSP70 affect the homeostasis. Diabetes leads to several microvasculature and microvasculature diseases like retinopathy, Toll like receptors are integral part of innate immune system and eHSP70 binds to toll like receptors and activates the MyD88 pathway, further stimulating NF-kB, cytokines like TNFα and IL1 β, increased production of reactive oxygen species contributing to insulin resistance and diabetes. Whereas there is decrease in the levels of iHSP70.<ref>{{cite journal | vauthors = Mulyani WR, Sanjiwani MI, Prabawa IP, Lestari AA, Wihandani DM, Suastika K, Saraswati MR, Bhargah A, Manuaba IB | display-authors = 6 | title = Chaperone-Based Therapeutic Target Innovation: Heat Shock Protein 70 (HSP70) for Type 2 Diabetes Mellitus | journal = Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy| volume = 13 | pages = 559–568 | date = February 2020 | pmid = 32161482 | doi = 10.2147/dmso.s232133 | pmc = 7051252 | doi-access = free }}</ref>
== In cardiovascular diseases ==
HSP70 is a chaperone with ubiquitous presence.<ref>{{cite journal | vauthors = Havalová H, Ondrovičová G, Keresztesová B, Bauer JA, Pevala V, Kutejová E, Kunová N | title = Mitochondrial HSP70 Chaperone System-The Influence of Post-Translational Modifications and Involvement in Human Diseases | journal = International Journal of Molecular Sciences | volume = 22 | issue = 15 | pages = 8077 | date = July 2021 | pmid = 34360841 | doi = 10.3390/ijms22158077 | pmc = 8347752 | doi-access = free }}</ref> It is crucial in the cardiovascular system. HSP70 normally aids in protein folding and aggregation; when present in the cell, functioning as an anti-inflammatory molecule; however, under stress conditions, it is localized to the extracellular milieu, where it is involved in inducing inflammatory pathways and contributes to disease pathogenesis.<ref>{{cite journal | vauthors = Linder M, Pogge von Strandmann E | title = The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells | journal = Cancers | volume = 13 | issue = 18 | pages = 4721 | date = September 2021 | pmid = 34572948 | doi = 10.3390/cancers13184721 | pmc = 8466959 | doi-access = free }}</ref> It is well established that intracellular HSP70 (iHSP70) levels play a protective role, whereas extracellular HSP70 (eHSP70) levels in circulating blood are linked to pathophysiology in micro and microvasculature, which results in a variety of cardiovascular illnesses. HSP70 homologues identified in human cytosol includes HSPA1A, HSPA1B, HSPA1L, HSPA12B, HSPA13, HSPA14 whereas HSPA9 in mitochondria. The HSP70 acts as DAMP and activates innate immune response which as involved in cardiovascular disease progression.<ref>{{cite journal | vauthors = Cai WF, Zhang XW, Yan HM, Ma YG, Wang XX, Yan J, Xin BM, Lv XX, Wang QQ, Wang ZY, Yang HZ, Hu ZW | display-authors = 6 | title = Intracellular or extracellular heat shock protein 70 differentially regulates cardiac remodelling in pressure overload mice | journal = Cardiovascular Research | volume = 88 | issue = 1 | pages = 140–149 | date = October 2010 | pmid = 20542874 | doi = 10.1093/cvr/cvq182 }}</ref>
The chaperone protein acts as auto antigen in atherosclerosis. Increased oxidative stress causes the formation of high-density oxidized LDL, the first event in the formation of plaque. This activates HSP70 and its promoter in the endothelial and smooth muscle cells, which contributes to atherosclerosis by inducing JAK/STAT pathway expression.<ref>{{cite book | vauthors = Wick C | title = Chaperokine Activity of Heat Shock Proteins | chapter = Heat Shock Protein 60: A Mediator of Atherosclerosis and Its Potential Therapeutic Role |date=2019 | doi = 10.1007/978-3-030-02254-9_4 | volume = 16 |pages=81–103 |place=Cham |publisher=Springer International Publishing |isbn=978-3-030-02253-2 | s2cid = 104325416 }}</ref><ref>{{cite journal | vauthors = Leng X, Wang X, Pang W, Zhan R, Zhang Z, Wang L, Gao X, Qian L | display-authors = 6 | title = Evidence of a role for both anti-Hsp70 antibody and endothelial surface membrane Hsp70 in atherosclerosis | journal = Cell Stress & Chaperones | volume = 18 | issue = 4 | pages = 483–493 | date = July 2013 | pmid = 23334859 | doi = 10.1007/s12192-013-0404-4 | pmc = 3682019 }}</ref>
HSP70 is also linked to high blood pressure, a worldwide concern and risk factor for a variety of cardiovascular diseases. Hypertension causes endothelial dysfunction and vascular wall damage, both of which contribute to arterial stiffness and atherosclerosis.<ref>{{cite journal | vauthors = Gallo G, Volpe M, Savoia C | title = Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications | journal = Frontiers in Medicine | volume = 8 | pages = 798958 | date = 2022-01-20 | pmid = 35127755 | doi = 10.3389/fmed.2021.798958 | pmc = 8811286 | doi-access = free }}</ref> HSPA1A, HSPA1B, and HSPA1L are three genes in humans that encode HSP70, and their polymorphism is linked to the onset of high blood pressure and cardiovascular disease.<ref name="Chen-2023">{{cite journal | vauthors = Chen Y, Zhao G, Li N, Luo H, Wang X, Gu J | title = [Corrigendum] Role of 4‑aminobutyrate aminotransferase (ABAT) and the lncRNA co‑expression network in the development of myelodysplastic syndrome | journal = Oncology Reports | volume = 49 | issue = 1 | pages = 1223–1229 | date = January 2023 | pmid = 36416343 | doi = 10.1161/01.cir.92.5.1223 | pmc = 9685366 }}</ref> Angiotensin II, endothelin-1, or phenylepinephrine cause HSP70 overexpression, which activates several molecular pathways, resulting in increased production of ROS, CRP, IL-10, TNF-alpha, and IL-6 <ref>{{cite journal | vauthors = Srivastava K, Narang R, Bhatia J, Saluja D | title = Expression of Heat Shock Protein 70 Gene and Its Correlation with Inflammatory Markers in Essential Hypertension | journal = PLOS ONE | volume = 11 | issue = 3 | pages = e0151060 | date = 2016-03-18 | pmid = 26989902 | doi = 10.1371/journal.pone.0151060 | pmc = 4798713 | bibcode = 2016PLoSO..1151060S | doi-access = free }}</ref><ref name="Chen-2023" /> These inflammatory signals interfere with the antioxidant machinery and results in rapid disease progression.
HSP70 expression increases after the coronary bypass surgery. Exercise has a positive and protective impact on cardiovascular disorders and stimulates the increased production of chaperone protein together known to be cardioprotective.
== Family members ==
Prokaryotes express three Hsp70 proteins: '''DnaK''', '''HscA (Hsc66)''', and '''HscC (Hsc62)'''.<ref name="pmid12054669">{{cite journal | vauthors = Yoshimune K, Yoshimura T, Nakayama T, Nishino T, Esaki N | title = Hsc62, Hsc56, and GrpE, the third Hsp70 chaperone system of Escherichia coli | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 5 | pages = 1389–95 | date = May 2002 | pmid = 12054669 | doi = 10.1016/S0006-291X(02)00403-5 }}</ref>
Eukaryotic organisms express several slightly different Hsp70 proteins. All share the common domain structure, but each has a unique pattern of expression or subcellular localization. These are, among others:
* '''[[HSPA8|Hsc70]]''' (Hsp73/HSPA8) is a constitutively expressed chaperone protein. It typically makes up one to three percent of total cellular protein.
* '''Hsp70''' (encoded by three very closely related paralogs: [[HSPA1A]], [[HSPA1B]], and [[HSPA1L]]) is a stress-induced protein. High levels can be produced by cells in response to hyperthermia, oxidative stress, and changes in [[pH]].
* [[Binding immunoglobulin protein]] ('''BiP''' or '''Grp78''') is a protein localized to the [[endoplasmic reticulum]]. It is involved in protein folding there, and can be upregulated in response to stress or starvation.
* '''[[HSPA9|mtHsp70]]''' or '''Grp75''' is the [[mitochondrion|mitochondrial]] Hsp70.
The following is a list of human Hsp70 genes and their corresponding proteins:<ref name="pmid9222585" />
{| class="wikitable"
|-
! gene
! protein
! synonyms
! subcellular location
|-
| [[HSPA1A]]
| Hsp70
| HSP70-1, Hsp72
| [[Cell nucleus|Nuc]]/[[Cytoplasmic|Cyto]]
|-
| [[HSPA1B]]
| Hsp70
| HSP70-2
| Nuc/Cyto
|-
| [[HSPA1L]]
| Hsp70
|
| ?
|-
| [[HSPA2]]
| Hsp70-2
|
| ?
|-
| [[Binding immunoglobulin protein|HSPA5]]
| Hsp70-5
| BiP/Grp78
| [[Endoplasmic reticulum|ER]]
|-
| [[HSPA6]]
| Hsp70-6
|
| ?
|-
| [[HSPA7]]
| Hsp70-7
|
| ?
|-
| [[HSPA8]]
| Hsp70-8
| Hsc70
| Nuc/Cyto
|-
| [[HSPA9]]
| Hsp70-9
| Grp75/mtHsp70
| [[Mitochondrion|Mito]]
|-
| [[HSPA12A]]
| Hsp70-12a
|
| ?
|-
| [[HSPA14]]
| Hsp70-14
|
| ?
|}
HSP70s are found in many [[plant]]s including [[Arabidopsis thaliana|Arabidopsis]], [[soybean]] (''Glycine max''), [[barley]] (''Hordeum vulgare'') and [[wheat]] (''Triticum aestivum'').<ref name = "HSP70" >{{cite journal | vauthors = Berka M, Kopecká R, Berková V, Brzobohatý B, Černý M | title = Regulation of heat shock proteins 70 and their role in plant immunity | journal = Journal of Experimental Botany | volume = 73 | issue = 7 | pages = 1894–1909 | date = April 2022 | pmid = 35022724 | doi = 10.1093/jxb/erab549 | publisher = [[Oxford University Press]] (OUP) | pmc = 8982422 | id = [[Society for Experimental Biology]] (SEB) | department = Review Paper | doi-access = free }}</ref>
=== Hsps 90 and 110 ===
[[File:Hsp90 Regulation.png|thumb|]]
Hsp90s are essential for protein remodeling, similar to Hsp70 proteins, and play an especially vital role in eukaryotes, where it has been suggested that Hsp90 interacts with the DnaK system (composed of DnaK, GrpE, and either DnaJ or CbpA) to facilitate the process of protein remodeling.<ref name="GenestHoskins2011">{{cite journal | vauthors = Genest O, Hoskins JR, Camberg JL, Doyle SM, Wickner S | title = Heat shock protein 90 from Escherichia coli collaborates with the DnaK chaperone system in client protein remodeling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 20 | pages = 8206–11 | date = May 2011 | pmid = 21525416 | doi = 10.1073/pnas.1104703108 | pmc = 3100916 | bibcode = 2011PNAS..108.8206G | doi-access = free }}</ref> In E. coli, Hsp90s works collaboratively with Hsp70s to facilitate protein remodeling and activation. Hsp90Ec and DnaK are chaperones of Hsp90 and Hsp70, respectively. DnaK initially binds and stabilizes the misfolded protein before working collaboratively with Hsp90Ec to refold this substrate and cause its activation. Given conditions of excess DnaK, this chaperone has been found to inhibit remodeling of proteins. However, the presence of Hsp90Ec can mitigate this effect and enable protein remodeling despite conditions of excess DnaK.<ref name="GenestWickner2019">{{cite journal | vauthors = Genest O, Wickner S, Doyle SM | title = Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling | journal = The Journal of Biological Chemistry | volume = 294 | issue = 6 | pages = 2109–2120 | date = February 2019 | pmid = 30401745 | doi = 10.1074/jbc.REV118.002806 | pmc = 6369297 | doi-access = free }}</ref>
The Hsp70 superfamily also includes a family of '''Hsp110'''/'''Grp170''' (Sse) proteins, which are larger proteins related to Hsp70.<ref name="hs-hsp-nom">{{cite journal | vauthors = Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE | display-authors = 6 | title = Guidelines for the nomenclature of the human heat shock proteins | journal = Cell Stress & Chaperones | volume = 14 | issue = 1 | pages = 105–11 | date = January 2009 | pmid = 18663603 | pmc = 2673902 | doi = 10.1007/s12192-008-0068-7 }}</ref> The Hsp110 family of proteins have divergent functions: yeast Sse1p has little ATPase activity but is a chaperone on its own as well as a nucleotide exchange factor for Hsp70, while the closely related Sse2p has little unfoldase activity.<ref name="pmid25487014"/>
The following is a list of currently named human HSP110 genes. HSPH2-4 are proposed names and the current name is linked:<ref name=hs-hsp-nom/>
{| class="wikitable"
|-
! gene
! synonyms
! subcellular location
|-
| [[HSPH1]]
|HSP105
| Cyto
|-
| [[HSPH2]]
| [[HSPA4]]; APG-2; HSP110
| Cyto
|-
| [[HSPH3]]
| [[HSPA4L]]; APG-1
| Nuc
|-
| [[HSPH4]]
| [[HYOU1]]/Grp170; ORP150; HSP12A
| ER
|}
== See also ==
* [[Heat shock protein 70 (Hsp70) internal ribosome entry site (IRES)]]
== References ==
{{Reflist|30em}}
External links
* {{MeshName|HSP70+Heat-Shock+Proteins}}
{{Chaperones}}
[[Category:Heat shock proteins]]
[[Category:Molecular chaperones]]