Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 10;25(8):4209.
doi: 10.3390/ijms25084209.

Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases

Manish Kumar Singh  1   2 , Yoonhwa Shin  1   2 , Songhyun Ju  1   2   3 , Sunhee Han  1   2   3 , Wonchae Choe  1   2   3 , Kyung-Sik Yoon  1   2   3 , Sung Soo Kim  1   2   3 , Insug Kang  1   2   3
Affiliations
Review

Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases

Manish Kumar Singh et al. Int J Mol Sci. .

Abstract

The heat shock response is an evolutionarily conserved mechanism that protects cells or organisms from the harmful effects of various stressors such as heat, chemicals toxins, UV radiation, and oxidizing agents. The heat shock response triggers the expression of a specific set of genes and proteins known as heat shock genes/proteins or molecular chaperones, including HSP100, HSP90, HSP70, HSP60, and small HSPs. Heat shock proteins (HSPs) play a crucial role in thermotolerance and aiding in protecting cells from harmful insults of stressors. HSPs are involved in essential cellular functions such as protein folding, eliminating misfolded proteins, apoptosis, and modulating cell signaling. The stress response to various environmental insults has been extensively studied in organisms from prokaryotes to higher organisms. The responses of organisms to various environmental stressors rely on the intensity and threshold of the stress stimuli, which vary among organisms and cellular contexts. Studies on heat shock proteins have primarily focused on HSP70, HSP90, HSP60, small HSPs, and ubiquitin, along with their applications in human biology. The current review highlighted a comprehensive mechanism of heat shock response and explores the function of heat shock proteins in stress management, as well as their potential as therapeutic agents and diagnostic markers for various diseases.

Keywords: apoptosis; heat shock factors; heat shock proteins; human disease; stress response; thermotolerance.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The diagram illustrates various stressors, including environmental stress, physiological stress, and physiological conditions, which trigger the activation and trimerization of HSFs. HSFs then translocate into the nucleus and activate the overexpression of stress genes such as heat shock proteins (HSPs).
Figure 2
Figure 2
The diagram illustrates HSPs and their associated functions. HSPs (HSP100, HSP90, HSP70, HSP60, SHSPs, ubiquitin) oversee diverse cellular functions.
Figure 3
Figure 3
The diagram illustrates the HSP100/Clp protein domain arrangement (above) and HSP100 assisting protein folding (below). (A) HSP100/ClpB comprises three main domains, the substrate binding domain, middle domain, and C-terminal domain, as illustrated in Class-I and Class-II. (B) It facilitates the folding of nascent polypeptides and misfolded proteins in an ATP-dependent manner. ATP is required for activating protein folding and binding of HSP70/40. Upon proper folding of protein, ATP is hydrolyzed, leading to dissociation of the HSP70/40 complex, and the folded protein is released into the cytoplasm.
Figure 4
Figure 4
The diagram illustrates the HSP90/HSPC protein domain arrangement (above) and HSP90 interacting client proteins (below). (A) HSP90/HSPC consists of three main domains, the ATP binding domain, middle domain, and C-terminal domain. The C-terminal domain contains highly conserved sequences that help in dimerization. (B) HSP90 has many interactors that bind to the middle domain (206–287 amino acids) region and regulate various functions in the cells. Solid ‘→’ shows direct interaction, doted ‘→’ intermittent function.
Figure 5
Figure 5
The diagram depicts the domain arrangement of the HSP70/HSPA/B protein (above) and its associated functions (below). (A) HSP70 comprises two main domains: the ATPase domain and the C-terminal domain. ATP is necessary for activating protein folding by binding to the ATPase domain. (B) HSP70 is implicated in various biological functions. The diagram illustrates its involvement in cellular pathways such as mitochondrial integrity, apoptosis, protein folding, inflammatory responses, and disease regulation. It also represents HSP70’s interactions with other cellular proteins such as p53, TNFα, MAPK, and Apaf-1, which regulate cancer, hypoxia, inflammation, and apoptosis. Loss of the mitochondrial membrane potential leads to apoptotic cell death. Green circle: phosphorylated-STAT1; Marron triangle: FAS-ligands, Violet circle: Fas-associated Protein death domain; Sky-blue oval: Pro-caspase-8; Red box: p53.
Figure 6
Figure 6
The diagram depicts the HSP60/HSPD protein domain arrangement (above), and its activation and functions (below). (A) HSP60/GroEL comprises three main domains, the equatorial domain, intermediate domain, and apical domain. (B) The diagram illustrates the involvement of HSP60 in various biological processes. It delineates different cellular pathways such as mitochondrial integrity, apoptosis, protein folding, inflammatory responses, and disease regulation associated with HSP60. HSP60 interacts with other cellular proteins such as BAX, NF-kβ, IKK, and p38 to regulate cancer, diabetes, neurodegeneration, inflammation, and apoptosis. Various stressors and chemical and physical activations of downstream signals regulate protein folding and cell death pathways. Mitochondrial dysfunction and loss of membrane integrity lead to activation of cell death via apoptosis. Abbreviations: Alzheimer’s disease (AD), Parkinson’s disease (PD), Human immunodeficiency virus disease (HIV), Rheumatoid arteritis (RA). Red circle: Chemical stress inducers; Green circle: Activated molecules bind to DNA, Marron triangle: Death ligands; Violet circle: Fas-associated Protein death domain; Sky blue oval: Pro-caspase-8; Green box: BAX; Red box: BAK.
Figure 7
Figure 7
The diagram illustrates the domain arrangement of the HSP27/HSPB protein (above), and HSP27-associated functions (below). (A) HSP27, comprising the N-terminal domain, α-crystallin domain, and C-terminal domain. (B) The diagram depicts the HSP27 involved in various cellular pathways. The diagram illustrates HSP27 involved in various crucial processes including mitochondrial integrity, apoptosis, protein folding, and cell cycle regulation. HSP27 interacts with cellular proteins such as Bim, cytochrome C, and DAXX, thereby modulating processes regulated to cancer, neurodegeneration, and apoptosis. Various stressors and chemical and physical stimuli activate downstream signals that regulate protein folding and cell death pathways. Dysfunctional mitochondria and compromised membrane integrity trigger cell death through apoptosis. Red circle: Chemotherapeutic drug; Green circle: Active chemotherapeutic drugs; Marron triangle: Death ligands, Violet circle: Fas-associated Protein death domain; Sky-blue oval: Pro-caspase-8; Red box: Bim.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Schumann W. Thermosensors in eubacteria: Role and evolution. J. Biosci. 2007;32:549–557. doi: 10.1007/s12038-007-0054-8. - DOI - PubMed
    1. Morimoto R.I., Santoro M.G. Stress–inducible responses and heat shock proteins: New pharmacologic targets for cytoprotection. Nat. Biotechnol. 1998;16:833–838. doi: 10.1038/nbt0998-833. - DOI - PubMed
    1. Tissiéres A., Mitchell H.K., Tracy U.M. Protein synthesis in salivary glands of Drosophila melanogaster: Relation to chromosome puffs. J. Mol. Biol. 1974;84:389–398. doi: 10.1016/0022-2836(74)90447-1. - DOI - PubMed
    1. McKenzie S.L., Meselson M. Translation in vitro of Drosophila heat-shock messages. J. Mol. Biol. 1977;117:279–283. doi: 10.1016/0022-2836(77)90035-3. - DOI - PubMed
    1. Lindquist S. Regulation of protein synthesis during heat shock. Nature. 1981;293:311–314. doi: 10.1038/293311a0. - DOI - PubMed

Substances