Heat shock protein Hsp70: prerequisites for use as a medicinal product

Cite item


Heat shock protein Hsp70 is one of the main cytoprotection components under the action of various external stimuli. The analysis of the literature data shows that nowadays, the researches’ overwhelming evidence has proven the role of Hsp70 as a biological target for the drug development; however, the ideas about its use as a drug are often multidirectional.

The aim of the article is to analyze and generalize the literature data on the features of the physiological functions of heat shock protein Hsp 70, and indicate the possibilities of its use for the pharmacological correction of various pathological conditions.

Materials and methods. In the process of selecting material for writing this review article, such databases as Google Patents, Science Research Portal, Google Scholar, ScienceDirect, CiteSeer, Publications, ResearchIndex, Ingenta, PubMed, KEGG, etc. were used The following words and word combinations were selected as markers for identifying the literature: Hsp70, Hsp70 stroke, Hsp70 neuroprotection, Hsp70 cytoprotection, recombinant drugs.

Results. In this review, the pharmacology of one of the key members of this family, Hsp70, was focused on. The literary analysis confirms that this molecule is an endogenous regulator of many physiological processes and demonstrates tissue protective effects in modeling ischemic, neurodegenerative and inflammatory processes. The use of recombinant exogenous Hsp70 mimics the endogenous function of the protein, indicating the absence of a number of typical limitations characteristic of pharmacotherapy with high molecular weight compounds, such as immunogenicity, a rapid degradation by proteases, or a low penetration of histohematogenous barriers.

Conclusion. Thus, Hsp70 may become a promising agent for clinical trials as a drug for the treatment of patients with neurological, immunological, and cardiovascular profiles.

Full Text

Abbreviations: MPs – medicinal products; ALS – amyotrophic lateral sclerosis; Hsp – heat schock protein; HSF1 – heat protein factor 1 / heat shock factor 1; HSEs – heat shock elements; TNF – tumor necrosis factor; PRRs – pattern recognition receptor; SBDa – sphingolipid binding domain alfa; NBD – nucleotid binding domen; NEF – nucleotide exchange factor; DISC – DISC-death-inducing signaling complex; BAG-1 – BAG family molecular chaperone regulator 1; CHIP – carboxyl terminus of Hsc70-interacting protein; E3 – ubiquitin-protein isopeptide ligase; TRAIL – TNF-related apoptosis-inducing ligand; BID – pro-apoptotic member of the Bcl-2 family; FANCC – Fanconianemia complementation group C; PKR – proteinkinasa R; MCA – middle cerebral artery; 17-DMAG – 17-demetoxigeldanamycin; NF-kB – nuclear factor-kappa B; AIF – apoptosis inducing factor; UPS – ubiquitin- proteasome system; JNK – Jun N-terminal kinases; Hip – hunting interacting protein; Hop – hunting interacting protein; Hsp 70-1 – Heat shock 70 kDa protein 1; DR4 – death receptor 4; DR5 – death receptor 5; p53 – protein p53; rhHsp70 – recombinant human heat schock protein 70; NMDA – N-methyl-D-aspartate receptor; IL-6 – Interleukin 6; TNF-α – Tumor necrosis factor-alpha; IL-1β, – Interleukin 1β; MCP-1 – monocyte chemotactic protein; TLRs – Toll-like receptors; DAMP – damage-associated molecular pattern; FasR – Fas-receptor; SMAC – the second mitochondrial activator of caspase; MAPK mitogen-activated protein kinase; ICAD – inhibitor of caspase-activated DNase; IKK – kappa B inhibitor kinase; Apaf 1 – apoptosis protease activating factor-1; СCP – cellular cytosolic protein; MMPs – matrix metalloproteinases; Mcl-1 – myeloid Cell Leukemia differentiation protein 1; ASK1 – apoptosis signal-regulating kinase 1; BBB – blood-brain barrier; Casp 9 – caspase 9; FADD – Fas-associated death domain.


Protein homeostasis in mammals has been maintained by a multicomponent system of proteins that regulate metabolic processes. That system depends on environmental conditions. The hypothesis of the existence of a heat shock proteins family, the first mention of which dates back to 1962, was put forward on the basis of the discovery of mammalian tissues’ tolerance phenomenon to high temperatures after a sharp heating of the same tissue site to sublethal temperatures [1].

Currently, many studies aimed at studying the spatial form, molecular interactions and physiological functions of heat shock proteins, have been carried out [2, 3]. The proteomics of a large family of chaperones, the function of which is traditionally associated with the folding and assembly of proteins, has been described. Molecular chaperones play an important role in proteostasis. In particular, Hsp70 means a lot in protein coagulation, disaggregation, and degradation [4]. Through substrate-binding domains, Hsp70 interacts with a wide range of molecules, providing cytoprotective properties against cellular stresses of various etiologies. The functions variety of heat shock proteins prompts the need to study their behavior in various pathological conditions. In eukaryotic cells, in physiological and pathological terms, there are four main pathways of protein degradation: the ubiquitin-proteasome system and three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy [5]. Hsp70 provides specificity in the choice of substrate for all types of the above listed processes. In the literature, different variants of this protein name can be found: heat shock protein 70 kDa, Hsp70, chaperone Hsp70, and Hsp73.

The multitude of Hsp70 physiological functions determine the researchers’ interest in studying the possibilities of its use in various pathological conditions. Heat shock proteins occupy one of the important positions in all the variety of folding proteins in mammalian bodies. At the same time, the use of these chaperones is hard due to the high cost of their production using producers’ bacterial strains. Recombinant drugs are the substances obtained by artificial means based on genetic engineering. At the moment, in the classification of recombinant drugs, pharmacologists distinguish 2 main groups: protein recombinant drugs and hormonal recombinant drugs. With the help of recombinant DNA, more than 400 genes (mainly in the form of cDNA) of various human proteins that are or can become drugs have been cloned. The analysis of the biotechnology market shows that the annual volume of the world drug market based on human proteins is about $ 150 billion and is constantly growing [6]. The advantage of biopharmaceuticals lies in their high targeting action, which is associated with a reduced risk of side effects in comparison with conventional low molecular weight drugs [7]. Biotechnological drugs have found application in the treatment of patients with pronounced adverse reactions to traditional synthetic drugs [8]. Modern methods of creating transgenic animal producers of recombinant proteins open up new prospects for their use aimed at the pharmacological correction of pathological conditions associated with a violation of the structural organization of protein molecules. This mini-review reflects the main mechanisms of functioning and molecular interaction of Hsp70 with effector molecules known to science in various pathological cascades. Taking into account the available literature data, the prospects of using this substance as a drug with neuroprotective and cytoprotective activities, are discussed.

THE AIM of the article is to analyze and generalize the literature data on the features of the physiological functions of heat shock protein Hsp 70, and indicate the possibilities of its use for the pharmacological correction of various pathological conditions.


In the process of selecting material for writing this review article, the databases of Google Patents, Science Research Portal, Google Scholar, ScienceDirect, CiteSeer, Publications, ResearchIndex, Ingenta, PubMed, KEGG, etc. were used The following words and phrases were selected for the selection of literature: Hsp70, Hsp70 stroke, Hsp70 neuroprotection, Hsp70 cytoprotection, recombinant drugs.


Basic Hsp 70 Biology

The human Hsp70 family of proteins includes 13 molecules that differ from each other in the expression level, a subcellular arrangement, and an amino acid composition. They are encoded by a polygenic family consisting of up to 17 genes and 30 pseudogenes [9]. The functional genes encoding human Hsp70 proteins are associated with several chromosomes. Major stress-induced Hsp70s chaperones include Hsp70-1 (HspA1A) and Hsp70-2 (HspA1B) proteins, referred to as Hsp70 or Hsp70-1 as a whole, differ from each other in only two amino acids. The expression of basal HSPA1A / B mRNA varies in most tissues and exceeds the expression levels of other Hsp70 isoforms in humans. Hsp70-1t (Heat shock 70 kDa protein 1) is a constitutive, non-inducible chaperone that is 90% identical to Hsp70-1 [10].

Hsp70 is known to consist of two main domains: the N-terminal nucleotide binding domain (NBD) (45 kDa) and the substrate binding domain (SBD) (25 kDa). The first is a V-shaped structure consisting of two subdomains (lobes) surrounding the ATP binding site. The second one also consists of two: a substrate binding domain beta (SBDβ) and a substrate binding domain alpha – (SBDa) [11].

Later data showed that chaperones perform a dual function in proteostasis, contributing to the implementation of the main stages of protein degradation [12]. The interaction of a particular chaperone with other chaperones or cochaperones determines the fate of the former through one of the common pathways of protein degradation, the ubiquitin-proteasome system (UPS), or autophagy. In eukaryotes, Hsp70 interacts with two cochaperones: J, the domain cochaperone, Hsp40, and the nucleotide exchange factor NEF. Hsp40 is known to stimulate ATP Hsp70 hydrolysis and can participate in the presentation of Hsp70 substrates [13, 14]. NEF promotes the exchange of nucleotides by Hsp70, inducing the release of ADP (Fig. 1) [15].


Figure 1 – Model of the Hsp70 oligomerization assembly line. Note: Cellular stress changes chaperone conformation, which facilitates Hsp 70 oligomerization. Co-chaperones and associated substrates bind to Hsp 70 oligomer, forming active chaperone complex


It has been proven that normally, Hsp70 plays several roles in signaling cascades involved in the cell growth and differentiation. The molecular mechanism of Hsp70 induction regulation depends on the activity of a unique heat shock transcription factor 1 (HSF1), which binds to the 5’-promoter regions of all Hsp genes and triggers the transcription. Under homeostatic conditions, Hsp70 is intracellular and associated with HSF1 [16]. High temperature, ischemia, and other causes for the accumulation of unfolded proteins lead to Hsp70 dissociation from HSF, leaving it free for target proteins to bind. In the stressed cell, dissociated HSF is transported to the nucleus, where it is phosphorylated, possibly by protein kinase C, to form activated trimers. The resulting trimers bind to the highly conservative regulatory sequences of the heat shock gene known as heat shock elements (HSEs). HSEs bind to the promoter region of the inducible gene Hsp70, which leads to an increase in the Hsp70 generation [17]. Through binding to HSF1, Hsp90 can also affect Hsp70: when Hsp90 dissociates with HSF1, the latter is released to bind HSEs and leads to an even greater Hsp70 induction [18].

The newly generated Hsp70 in combination with ATP, Hsp40 and Hsp90 binds to denatured proteins and acts as a molecular chaperone, promoting the repair, clotting and transport of damaged peptides within the cell. Subsequently, a complex is formed, which includes the Hip (hunting-interacting protein) and Hop (hunting-organizing protein) associated with the N and C terminal domains, respectively, due to which clotting and then refolding of denatured structures occurs [19]. If no clotting occurs, BAG-1 binds to the N-terminus of Hsp70, and CHIP E3 ubiquitin ligase binds to the C-terminus of Hsp70. This complex then interacts with the denatured protein and recruits it into proteasome [20]. Thus, Hsp70 is involved in the damaged proteins refolding.

Interaction of Hsp70 with some of the pro- and anti-apoptotic proteins

A stress-induced expression of Hsp70 allows cells to cope with a large number of unfolded and / or denatured proteins resulting from the external stress. Traditionally, such typical pathological processes include inflammation, hypoxia, apoptosis, and tumor growth [21].

Apoptosis, as the body’s response to pathological changes, is involved in the pathogenetic links of many diseases, such as strokes, neonatal hypoxia, degenerative retinal diseases, graft rejection, Alzheimer’s disease and other neurodegenerative diseases [21, 22].

Caspase-independent and caspase-dependent apoptosis pathways are distinguished. The caspase-dependent pathway of apoptosis is divided into internal and external. Complex signaling pathways occur in the cell from the initiation to the start of a signaling molecules cascade, including many proteins. It is obvious that the impact on any element of this cascade can be a therapeutic target for a pharmacological correction of apoptosis processes. For example, nerve growth factors inhibit apoptosis and appear to meet therapeutic needs in diseases with extensive autolysis. An increase in Bcl-2 expression can inhibit pathological neuronal apoptosis in response to neurotoxic factors. In addition, it has been proven that low molecular weight caspase inhibitors, for example, Z-VAD-FMK, are effective in the treatment of amyotrophic lateral sclerosis in animals [23].

Apoptosis is required to maintain cellular homeostasis. The Hsp70 expression increases the cell survival under stress. Hsp70 knockdown cells are sensitive to autolysis [24], while the Hsp70 overexpression inhibits apoptosis, acting either through the internal Akt / PKB mitochondria-dependent or the external receptor-dependent pathway [25].

External apoptosis is initiated by plasma membrane-bound proteins of the TNF receptor family, which lead to the activation of caspase-8/10 in the death-inducing signaling complex (DISC) [26]. Hsp70 can also inhibit the assembly of the DISC signaling complex, inhibiting apoptosis induced by Fas, TRAIL, and TNF. After TNF-induced DISC formation and activation of caspase 8, Hsp70 can inhibit BID activation [27]. When interacting with an extracellular ligand, membrane receptors transmit death signals to the intracellular space through their cytoplasmic domains. The membrane receptors involved in apoptosis belong to the superfamily of tumor necrosis factor (TNF) receptors, the activation of which depends on two main ligands: TNF and Fas. TNF and its receptors, namely TNFR-1 and TNFR-2, are responsible for initiating the main apoptosis pathway, i.e. the TNF pathway. The interaction between TNF and its receptors has been shown to signal death by recruiting two adaptive proteins: the TNF receptor-associated death domain (TRADD) and the Fas-associated death domain (FADD) protein. A cascade of these processes affects programmed cell death through the action of caspases. FNO ligands form homotrimers that bind to FNO receptors on the membrane [28]. In TNF-α-induced apoptosis, Hsp70 interacts with the FANCC protein (Fanconianemia complementation group C, PKR inhibitor) through its ATP domain and forms a triple complex with FANCC and PKR [29, 30]. It also resists TRAIL-induced apoptosis and the formation of a death-causing signaling complex with death receptors DR4 and DR5 [31]. The Hsp70 function in Fas-induced apoptosis is under-explored, but the adverse effects depend on the cellular context [32].

The internal apoptotic pathway is initiated by the release of various factors from the cell mitochondria. In response to the brain damage and the resulting oxidative stress, a transitional pore of permeability is formed in mitochondria. That leads to the release of cytochrome C into the cytosol, where a number of pro-apoptotic molecules ultimately cause the activation of effector caspases. Among these molecules, there are Bcl-2 family proteins, some of which are pro-apoptotic. These molecules are the main regulators of the mitochondrial membrane. Bcl2 and Bax are targets for the suppressor protein of p53 tumor. In response to DNA damage, Bcl2 transcription is repressed, and Bax is induced [33, 34]. Tumor cells often have mutated p53 that forms a stable complex with Hsp70 / Hsc70. A stress-mediated expression of Hsp70 inhibits nuclear import of p53 [35]. However, the Hsp70 regulation of the NF-kB function is still under-explored. Cytosolic Hsp70 can inhibit the expression of NF-kB, and membrane-bound Hsp70 can induce this transcription factor [36]. In neuronal stem cells, the Hsp70 induction by the recombination plasmid pEGFP-C2-HSP70 significantly blocks caspase-3 and reduces neuronal cytotoxicity, including a neuronal loss and a synapse damage in cocultured cells [37]. After an inflammatory stimulus, oligodendrocyte progenitor cells and mature oligodendrocytes from mice deficient in Hsp70 come into apoptosis caused by the caspase-3 activation [38]. Fig. 2 shows some of the apoptotic proteins that Hsp70 interacts with.


Figure 2 – Interaction of Hsp70 with apoptosis and inflammation regulating proteins


Experience in pharmacological use of recombinant Hsp70

Neuroprotective action

Studies confirming the neuroprotective role of endogenous heat shock proteins [39] have stimulated the development of pharmacological strategies based on the use of recombinant human Hsp70 [40]. Thus, Xinhua Zhan et al. demonstrated that the administration of Fv-Hsp70 2 and 3 hours after focal cerebral ischemia resulted in a 68% decrease in the volume of the infarction zone and significantly improved sensorimotor functions compared to the control group [41]. Similar results were presented in the publication by a Russian scientific group under the guidance of M.A. Shevtsov. The authors demonstrated that both preliminary and postischemic intravenous administration of rhHsp70 dose-dependently reduced the zone. Moreover, a long-term treatment of ischemic rats with rhHsp70 in the form of alginate granules with a sustained protein release further reduced the infarction volume and the apoptosis zone [42].

Similarly, the intranasal rhHsp70 administration resulted in a two-fold decrease in the local ischemia volume in the prefrontal cortex in the study of the mice with a photothrombotic stroke. In addition, the intranasal rhHsp70 administration reduced the level of apoptosis in the ischemic penumbra, stimulated axonogenesis, and increased the number of synaptophysin-producing neurons. In an isolated crayfish mechanoreceptor consisting of a single sensory neuron surrounded by a glial membrane, exogenous Hsp70 significantly reduced photoinduced apoptosis and necrosis of glial cells [43].

Moreover, as a therapeutic agent for slowing down neurodegenerative processes, rhHsp70 also demonstrates a high potential. In the study by David J. Gifondorwa et al., recombinant human Hsp70 delayed the onset of paralysis in a murine model of amyotrophic lateral sclerosis caused by overexpression of the mutant SOD1 gene. When administered intraperitoneally three times a week, starting from the 50th day of life, rhHsp70 led to an increase in life expectancy, a delay in the onset of symptoms, preservation of motor function, and an increase in the number of innervated neuromuscular connections compared with the control tissue [44].

In the transgenic mouse model of Alzheimer’s disease and in the mice with bulbectomy, intranasally administered rhHsp70 quickly penetrates the affected areas of the brain and mitigates multiple morphological and cognitive anomalies, normalizing the density of neurons in the hippocampus and cortex of the brain and reducing the accumulation of amyloid-β and amyloid plaques [45, 46].

In addition to the direct cytoprotective activity against neurons, rhHsp70 demonstrates a GABA-ergic effect: a preliminary intracerebroventricular administration of Hsp70 reduces the severity of the seizures caused by NMDA- and pentylenetetrazole. Moreover, traced Hsp70 in neurons was co-localized with NMDA receptors, synaptophysin, and L-glutamic acid decarboxylase [47].

Anti-inflammatory activity

A preventive Hsp70 administration reduced the toxic effect of E. coli endotoxin on the rat organism and significantly increased the survival rate of the animals during the experiment [48, 49]. In addition, in the models of sepsis caused by the administration of lipoteichoic acid, it was shown that the prophylactic administration of exogenous human Hsp70 significantly attenuates numerous homeostatic and ehmodynamic disorders and partially normalizes the coagulation system disorders and many biochemical blood parameters, including the concentrations of albumin and bilirubin [50, 51].

It has been shown that both intracellular and extracellular Hsp70 modulates the activation of the key pro-inflammatory factor NF-kB [52]. Thus, overexpressed Hsp70 blocks the NF-kB activation and p50/p65 nuclear translocation by inhibiting IKK-mediated phosphorylation of IkB (NF-kB inhibitor). It is of interest to note that the opposite effect occurs when Hsp70 is outside the cell. It is assumed that extracellular Hsp70 can act as a damage-associated molecular pattern (DAMP) through the innate immunity receptors TLR2 and TLR4 and thus trigger pro-inflammatory cascades. [53] An increase in the expression / secretion of NF-kB-dependent pro-inflammatory cytokines, including interleukin IL-1β, interleukin IL-6 and FNO-α, in response to extracellular Hsp70 in human lung cancer cells, dendritic cells and monocytes, was also notified. [54] However, other studies have shown that in the cultures of synoviocytes obtained from the patients with rheumatoid arthritis, extracellular Hsp70 inhibits the NF-kB signaling pathway, decreasing the level of IL-6, IL-8, and MCP-1 [55]. In addition, it has been shown that extracellular Hsp70 reduces the production of proinflammatory cytokines such as FNO-α and IL-6 in monocytes exposed to TLR agonists and contributes to the attenuation of the inflammatory response [56].

Thus, the results of a number of studies indicate that Hsp70 exhibits a predominantly anti-inflammatory activity, but under certain conditions it can activate pro-inflammatory cascades.

Modern methods for producing recombinant forms of Hsp70

Currently, it is known about the creation of Hsp70A1 recombinant forms. In particular, two sources are isolated: its isolation from the biomass of the E. coli bacterial culture, expressing it in increased quantities, and from transgenic mice-producers. To analyze its activity, the following parameters are determined: a substrate-binding activity, the analysis of the restoring activity of proteins, the ability to displace endogenous substance from the cells, the ability to reduce endotoxin-induced ROS production, and the ability to stimulate the natural killer cell activity towards the cancer cells in vitro. It is known that a protein glycosylation during the production can complicate the result of its administration to patients, especially when the body contains cells expressing the native form, causing an autoimmune response. A modified version of the protein was named rhHsp70.128, which differs fundamentally from the wild-type protein (rhHsp70.135) at five putative N-glycosylation sites: QGDRTTPSY, YFNDAQRQA, DLNKAINPD, KRNSAIPTK, and ILNVAATDK. A chaperone activity of the recombinant Hsp70 was assessed using carboxymethylated lactalbumin as a substrate protein. It was shown that the activity of the modified protein corresponds to the activity of the reference wild-type version and binds denatured lactalbumin with a similar efficiency. The next test consisted in measuring the activity of luciferase after its denaturation and recovery using the Hsp70 preparation in order to analyze its coagulability. The data show that all three tested samples were almost equally active. A series of experiments was also carried out to confirm the ability of the modified recombinant Hsp70 to displace its endogenous analogue from cells. Modified rhHsp70.128 as well as the wild-type probe, entered the cells and displaced endogenous Hsp70. An alternative way to obtain a recombinant Hsp protein, similar to that created in E. coli, was the creation of a female producers line expressing it in the mammary glands with a content of 1–2 mg/ml of protein in milk, depending on the animal. The study of its expression was carried out by the method of immunoblotting. It has been shown that the mutant protein can be efficiently isolated using ATP columns, as opposed to the wild type, by reacting to commercial antibodies. Based on the data obtained, it is obvious that the secretory production of the protein is technologically more advantageous in comparison with the cytoplasmic production due to the simplicity of its purification [57].


Chaperones are key regulators of cellular homeostasis that perform pleiotropic functions involving a wide range of signaling pathways. At the same time, heat shock proteins, the most studied family of chaperones, have a high pharmacotherapeutic potential for the treatment of a number of diseases associated with inflammation, apoptosis, and accumulation of misfolded proteins. This review was focused on the pharmacology of one of the key members of this family, Hsp70. The literature analysis confirms that this molecule is an endogenous regulator of many physiological processes and demonstrates tissue protective effects in modeling ischemic, neurodegenerative and inflammatory processes. The use of recombinant exogenous Hsp70 mimics the endogenous function of the protein, indicating the absence of a number of typical limitations characteristic of pharmacotherapy with high molecular weight compounds, such as immunogenicity, rapid degradation by proteases, or a low degree of passage through histohematogenous barriers. Thus, Hsp70 may become a promising agent for clinical trials as a drug for the treatment of patients with neurological, immunological, and cardiovascular profiles.


This study was supported by a grant from the Belgorod Region for the government support implementation of innovative technologies into promotion, within the framework of full-cycle technological projects.


The authors declare no conflict of interest.


Vladimir M. Pokrovsky – article planning and writing, reviewing references; Evgeniy A. Patrakhanov – reviewing references, formation list of references; Oleg V. Antsiferov – reviewing references, formation list of references; Inga M. Kolesnik – reviewing references, formation list of references; Anastasia V. Belashova – reviewing references, formation list of references; Valeria A. Soldatova – reviewing references, formation list of references; Olga N. Pokopeiko – reviewing references, formation list of references; Anastasia Yu. Karagodina – reviewing references, formation list of references; Ivan A. Arkhipov – reviewing references, formation list of references; Diana G. Voronina – reviewing references, formation list of references; Daria N. Sushkova – reviewing references, formation list of references.


About the authors

Vladimir M. Pokrovsky

Belgorod State National Research University (NRU “BelSU”)

Author for correspondence.
Email: vmpokrovsky@yandex.ru
ORCID iD: 0000-0003-3138-2075

6th year student

Russian Federation, 85, Pobeda St., Belgorod, 308015

Evgeniy A. Patrakhanov

Belgorod State National Research University (NRU “BelSU”)

Email: pateval7@gmail.com
ORCID iD: 0000-0002-8415-4562

6th year student of the Medical Institute

Russian Federation, 85, Pobeda St., Belgorod, 308015

Oleg V. Antsiferov

Belgorod State National Research University (NRU “BelSU”)

Email: antsiferov@bsu.edu.ru
ORCID iD: 0000-0001-6439-2419

Senior Lecturer, Department of Faculty Therapy

Russian Federation, 85, Pobeda St., Belgorod, 308015

Inga M. Kolesnik

Belgorod State National Research University (NRU “BelSU”)

Email: kolesnik_inga@mail.ru

sociate Professor of the Department of Pharmacology and Clinical Pharmacology

Russian Federation, 85, Pobeda St., Belgorod, 308015

Anastasia V. Belashova

Belgorod State National Research University (NRU “BelSU”)

Email: belashova_av@mail.ru
ORCID iD: 0000-0001-9737-6378

student of Medical Institute

Russian Federation, 85, Pobeda St., Belgorod, 308015

Valeria A. Soldatova

Belgorod State National Research University (NRU “BelSU”)

Email: lorsoldatova@gmail.com
ORCID iD: 0000-0002-9970-4109

postgraduate student of the Department of Pharmacology and Clinical Pharmacology

Russian Federation, 85, Pobeda St., Belgorod, 308015

Olga N. Pokopeiko

First Moscow State Medical University n. a. I.M. Sechenov (Sechenov University)

Email: OPokopejko@mail.ru

4th year student

Russian Federation, Bldg. 2, 8, Trubetskaya St., Moscow, 119991

Anastasia Yu. Karagodina

Belgorod State National Research University (NRU “BelSU”)

Email: anastasiavolmedic@gmail.com
ORCID iD: 0000-0001-9440-5866

6th year student, the Medical Institute

Russian Federation, 85, Pobeda St., Belgorod, 308015

Ivan A. Arkhipov

Belgorod State National Research University (NRU “BelSU”)

Email: iaarkhipovbsu@gmail.com

6th year student of the Medical Institute

Russian Federation, 85, Pobeda St., Belgorod, 308015

Diana G. Voronina

Belgorod State National Research University (NRU “BelSU”)

Email: diana0085@inbox.ru

Research Institute of Pharmacology of Living Systems

Russian Federation, 85, Pobeda St., Belgorod, 308015

Daria N. Sushkova

Belgorod State National Research University (NRU “BelSU”)

Email: maslova_d@bsu.edu.ru

Junior Researcher, Research Institute of Pharmacology of Living Systems

Russian Federation, 85, Pobeda St., Belgorod, 308015


  1. Schlesinger M.J. Heat shock proteins. J Biol Chem. 1990 Jul 25;265(21):12111-4.
  2. Ferat-Osorio E, Sánchez-Anaya A, Gutiérrez-Mendoza M, Boscó-Gárate I, Wong-Baeza I, Pastelin-Palacios R, Pedraza-Alva G, Bonifaz LC, Cortés-Reynosa P, Pérez-Salazar E, Arriaga-Pizano L, López-Macías C, Rosenstein Y, Isibasi A. Heat shock protein 70 down-regulates the production of toll-like receptor-induced pro-inflammatory cytokines by a heat shock factor-1/constitutive heat shock element-binding factor-dependent mechanism. J Inflamm (Lond). 2014 Jul 12;11:19. doi: 10.1186/1476-9255-11-19.
  3. Meng W, Clerico EM, McArthur N, Gierasch L. M. Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces. Proceedings of the National Academy of Sciences. 2018 Nov; 115(47):11970–75; doi: 10.1073/pnas.1811105115.
  4. Fernández-Fernández MR, Gragera M, Ochoa-Ibarrola L, Quintana-Gallardo L, Valpuesta JM. Hsp70 – a master regulator in protein degradation. FEBS Lett. 2017 Sep;591(17):2648–60. doi: 10.1002/1873-3468.12751.
  5. Acebrón SP, Fernández-Sáiz V, Taneva SG, Moro F, Muga A. DnaJ recruits DnaK to protein aggregates. J Biol Chem. 2008 Jan 18;283(3):1381–90. doi: 10.1074/jbc.M706189200.
  6. Assessment of Socio-Economic Development Forecast for the Russian Federation in 2019–2024. Finance: Theory and Practice. 2018;22(6):153–6. doi: 10.26794/2587-5671-2018-22-6-153-156. Russian
  7. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014 Sep;13(9):655–72. doi: 10.1038/nrd4363.
  8. Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des. 2013 Jan;81(1):136–47. doi: 10.1111/cbdd.12055.
  9. Brocchieri L, Conway de Macario E, Macario AJ. Hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol. 2008 Jan 23;8:19. doi: 10.1186/1471-2148-8-19.
  10. Daugaard M, Jäättelä M, Rohde M. Hsp70-2 is required for tumor cell growth and survival. Cell Cycle. 2005; 4 (Issue 7): 877–80. doi: 10.4161/cc.4.7.1838.
  11. Taylor IR, Ahmad A, Wu T, Nordhues BA, Bhullar A, Gestwicki JE, Zuiderweg ERP. The disorderly conduct of Hsc70 and its interaction with the Alzheimer’s-related Tau protein. J Biol Chem. 2018 Jul 6;293(27):10796–80. doi: 10.1074/jbc.RA118.002234.
  12. Doyle SM, Genest O, Wickner S. Protein rescue from aggregates by powerful molecular chaperone machines. Nat Rev Mol Cell Biol. 2013 Oct;14(10):617–29. doi: 10.1038/nrm3660.
  13. Acebrón SP, Fernández-Sáiz V, Taneva SG, Moro F, Muga A. DnaJ recruits DnaK to protein aggregates. J Biol Chem. 2008 Jan 18;283(3):1381–90. doi: 10.1074/jbc.M706189200.
  14. Ahmad A, Bhattacharya A, McDonald RA, Cordes M, Ellington B, Bertelsen EB, Zuiderweg ER. Heat shock protein 70 kDa chaperone/DnaJ cochaperone complex employs an unusual dynamic interface. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):18966–71. doi: 10.1073/pnas.1111220108.
  15. Bracher A, Verghese J. The nucleotide exchange factors of Hsp70 molecular chaperones. Front Mol Biosci. 2015 Apr 7;2:10. doi: 10.3389/fmolb.2015.00010.
  16. Gao T, Newton AC. The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. J Biol Chem. 2002 Aug 30;277(35):31585–92. doi: 10.1074/jbc.M204335200.
  17. Wang ML, Tuli R, Manner PA, Sharkey PF, Hall DJ, Tuan RS. Direct and indirect induction of apoptosis in human mesenchymal stem cells in response to titanium particles. J Orthop Res. 2003 Jul;21(4):697–707. doi: 10.1016/S0736-0266(02)00241-3.
  18. Zhao H, Michaelis ML, Blagg BS. Hsp90 modulation for the treatment of Alzheimer’s disease. Adv Pharmacol. 2012;64:1–25. doi: 10.1016/B978-0-12-394816-8.00001-5.
  19. Lanneau D, Wettstein G, Bonniaud P, Garrido C. Heat shock proteins: cell protection through protein triage. ScientificWorldJournal. 2010 Aug 3;10:1543–52. doi: 10.1100/tsw.2010.152.
  20. Alberti S, Demand J, Esser C, Emmerich N, Schild H, Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J Biol Chem. 2002 Nov 29;277(48):45920–7. doi: 10.1074/jbc.M204196200.
  21. Okafor CC, Haleem-Smith H, Laqueriere P, Manner PA, Tuan RS. Particulate endocytosis mediates biological responses of human mesenchymal stem cells to titanium wear debris. J Orthop Res. 2006 Mar;24(3):461–73. doi: 10.1002/jor.20075.
  22. Kobayashi SD, Voyich JM, Whitney AR, DeLeo FR. Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor. J Leukoc Biol. 2005 Dec;78(6):1408–18. doi: 10.1189/jlb.0605289.
  23. Lavrik IN, Golks A, Krammer PH. Caspases: pharmacological manipulation of cell death. J Clin Invest. 2005 Oct;115(10):2665–72. doi: 10.1172/JCI26252.
  24. Schmitt E, Parcellier A, Gurbuxani S, Cande C, Hammann A, Morales MC, Hunt CR, Dix DJ, Kroemer RT, Giordanetto F, Jäättelä M, Penninger JM, Pance A, Kroemer G, Garrido C. Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res. 2003 Dec 1;63(23):8233–40.
  25. Matsumori Y, Northington FJ, Hong SM, Kayama T, Sheldon RA, Vexler ZS, et al. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke 2006; 37 (Issue 2): 507–12. doi: 10.1161/01.STR.0000199057.00365.20.
  26. Guo F, Sigua C, Bali P, George P, Fiskus W, Scuto A, Annavarapu S, Mouttaki A, Sondarva G, Wei S, Wu J, Djeu J, Bhalla K. Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood. 2005 Feb 1;105(3):1246–55. doi: 10.1182/blood-2004-05-2041.
  27. Joly AL, Wettstein G, Mignot G, Ghiringhelli F, Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun. 2010;2(3):238–47. doi: 10.1159/000296508.
  28. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996 May 31;271(22):12687–90. doi: 10.1074/jbc.271.22.12687.
  29. Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC. FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. EMBO J. 2001 Aug 15;20(16):4478–89. doi: 10.1093/emboj/20.16.4478.
  30. Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC. The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. J Biol Chem. 2002 Dec 20;277(51):49638–43. doi: 10.1074/jbc.M209386200.
  31. Thirstrup K, Sotty F, Montezinho LC, Badolo L, Thougaard A, Kristjánsson M, Jensen T, Watson S, Nielsen SM. Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain. Pharmacol Res. 2016 Feb;104:197–205. doi: 10.1016/j.phrs.2015.12.028.
  32. Purandhar K, Jena PK, Prajapati B, Rajput P, Seshadri S. Understanding the role of heat shock protein isoforms in male fertility, aging and apoptosis. World J Mens Health. 2014 Dec;32(3):123–32. doi: 10.5534/wjmh.2014.32.3.123.
  33. Jiang B, Liang P, Deng G, Tu Z, Liu M, Xiao X. Increased stability of Bcl-2 in HSP70-mediated protection against apoptosis induced by oxidative stress. Cell Stress Chaperones. 2011 Mar;16(2):143–52. doi: 10.1007/s12192-010-0226-6.
  34. Crowe DL, Sinha UK. p53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines. Head Neck. 2006 Jan;28(1):15–23. doi: 10.1002/hed.20319.
  35. Akakura S, Yoshida M, Yoneda Y, Horinouchi S. A role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135). J Biol Chem. 2001 May 4;276(18):14649–57. doi: 10.1074/jbc.M100200200.
  36. Tsukahara F, Maru Y. Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70. J Biol Chem. 2004 Mar 5;279(10):8867–72. doi: 10.1074/jbc.M308848200.
  37. Lu D, Xu A, Mai H, Zhao J, Zhang C, Qi R, Wang H, Lu D, Zhu L. The synergistic effects of heat shock protein 70 and ginsenoside Rg1 against tert-butyl hydroperoxide damage model in vitro. Oxid Med Cell Longev. 2015;2015:437127. doi: 10.1155/2015/437127.
  38. Manucha W, Carrizo L, Ruete C, Vallés PG. Apoptosis induction is associated with decreased NHE1 expression in neonatal unilateral ureteric obstruction. BJU Int. 2007 Jul;100(1):191–8. doi: 10.1111/j.1464-410X.2007.06840.x.
  39. Manucha W, Kurbán F, Mazzei L, Benardón ME, Bocanegra V, Tosi MR, Vallés P. eNOS/Hsp70 interaction on rosuvastatin cytoprotective effect in neonatal obstructive nephropathy. Eur J Pharmacol. 2011 Jan 15;650(2-3):487–95. doi: 10.1016/j.ejphar.2010.09.059.
  40. Mansilla MJ, Costa C, Eixarch H, Tepavcevic V, Castillo M, Martin R, Lubetzki C, Aigrot MS, Montalban X, Espejo C. Hsp70 regulates immune response in experimental autoimmune encephalomyelitis. PLoS One. 2014 Aug 25;9(8):e105737. doi: 10.1371/journal.pone.0105737.
  41. Mazzei L, Docherty NG, Manucha W. Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy. Cell Stress Chaperones. 2015 Nov;20(6):893–906. doi: 10.1007/s12192-015-0622-z.
  42. Sharp FR, Lu A, Tang Y, Millhorn DE. Multiple molecular penumbras after focal cerebral ischemia. J Cereb Blood Flow Metab. 2000 Jul;20(7):1011–32. doi: 10.1097/00004647-200007000-00001.
  43. Doeppner TR, Nagel F, Dietz GP, Weise J, Tönges L, Schwarting S, Bähr M. TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2009 Jun;29(6):1187–96. doi: 10.1038/jcbfm.2009.44.
  44. Hulina A, Grdić Rajković M, Jakšić Despot D, Jelić D, Dojder A, Čepelak I, Rumora L. Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell Stress Chaperones. 2018 May;23(3):373–84. doi: 10.1007/s12192-017-0847-0.
  45. Zhan X, Ander BP, Liao IH, Hansen JE, Kim C, Clements D, Weisbart RH, Nishimura RN, Sharp FR. Recombinant Fv-Hsp70 protein mediates neuroprotection after focal cerebral ischemia in rats. Stroke. 2010 Mar;41(3):538–43. doi: 10.1161/STROKEAHA.109.572537.
  46. Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 1995;36(4):305–15. doi: 10.1007/BF00689048.
  47. Porter JR, Fritz CC, Depew KM. Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr Opin Chem Biol. 2010 Jun;14(3):412–20. doi: 10.1016/j.cbpa.2010.03.019.
  48. Doeppner TR, Ewert TA, Tönges L, Herz J, Zechariah A, ElAli A, Ludwig AK, Giebel B, Nagel F, Dietz GP, Weise J, Hermann DM, Bähr M. Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation. Stem Cells. 2012 Jun;30(6):1297–310. doi: 10.1002/stem.1098.
  49. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. doi: 10.1038/sigtrans.2017.23.
  50. Christian F, Smith EL, Carmody RJ. The Regulation of NF-κB Subunits by Phosphorylation. Cells. 2016 Mar 18;5(1):12. doi: 10.3390/cells5010012.
  51. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12:86. doi: 10.1186/1476-4598-12-86.
  52. Wang CH, Chou PC, Chung FT. et al. Heat shock protein70 is implicated in modulating NF-κB activation in alveolar macrophages of patients with active pulmonary tuberculosis. Sci Rep. 2017;7:1214. doi: 10.1038/s41598-017-01405-z.
  53. Hulina-Tomašković A, Somborac-Bačura A, Grdić Rajković M, Bosnar M, Samaržija M, Rumora L. Effects of extracellular Hsp70 and cigarette smoke on differentiated THP-1 cells and human monocyte-derived macrophages. Mol Immunol. 2019 Jul;111:53–63. doi: 10.1016/j.molimm.2019.04.002.
  54. Somensi N, Brum PO, de Miranda Ramos V, Gasparotto J, Zanotto-Filho A, Rostirolla DC, da Silva Morrone M, Moreira JCF, Pens Gelain D. Extracellular HSP70 Activates ERK1/2, NF-kB and Pro-Inflammatory Gene Transcription Through Binding with RAGE in A549 Human Lung Cancer Cells. Cell Physiol Biochem. 2017;42(6):2507–2522. doi: 10.1159/000480213.
  55. Luo X, Zuo X, Zhou Y, Zhang B, Shi Y, Liu M, Wang K, McMillian DR, Xiao X. Extracellular heat shock protein 70 inhibits tumour necrosis factor-alpha induced proinflammatory mediator production in fibroblast-like synoviocytes. Arthritis Res Ther. 2008;10(2):R41. doi: 10.1186/ar2399.
  56. Mortaz E, Redegeld FA, Nijkamp FP, Wong HR, Engels F. Acetylsalicylic acid-induced release of HSP70 from mast cells results in cell activation through TLR pathway. Exp Hematol. 2006 Jan;34(1):8–18. doi: 10.1016/j.exphem.2005.10.012.
  57. Gurskiy YG, Garbuz DG, Soshnikova NV, Krasnov AN, Deikin A, Lazarev VF, Sverchinskyi D, Margulis BA, Zatsepina OG, Karpov VL, Belzhelarskaya SN, Feoktistova E, Georgieva SG, Evgen’ev MB. The development of modified human Hsp70 (HSPA1A) and its production in the milk of transgenic mice. Cell Stress Chaperones. 2016 Nov;21(6):1055–1064. doi: 10.1007/s12192-016-0729-x.

Supplementary files

Supplementary Files
1. Figure 1 – Model of the Hsp70 oligomerization assembly line. Note: Cellular stress changes chaperone conformation, which facilitates Hsp 70 oligomerization. Co-chaperones and associated substrates bind to Hsp 70 oligomer, forming active chaperone complex

Download (126KB)
2. Figure 2 – Interaction of Hsp70 with apoptosis and inflammation regulating proteins

Download (94KB)

Copyright (c) 2021 Pokrovsky V.M., Patrakhanov E.A., Antsiferov O.V., Kolesnik I.M., Belashova A.V., Soldatova V.A., Pokopeiko O.N., Karagodina A.Y., Arkhipov I.A., Voronina D.G., Sushkova D.N.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 67428 от 13.10.2016. 

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies