Cellular stress response

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Cellular stress response is the wide range of molecular changes that cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage. Cellular stress responses can also be caused by some viral infections. [1] The various processes involved in cellular stress responses serve the adaptive purpose of protecting a cell against unfavorable environmental conditions, both through short term mechanisms that minimize acute damage to the cell's overall integrity, and through longer term mechanisms which provide the cell a measure of resiliency against similar adverse conditions. [2]

Contents

General characteristics

Cellular stress responses are primarily mediated through what are classified as stress proteins. Stress proteins often are further subdivided into two general categories: those that only are activated by stress, or those that are involved both in stress responses and in normal cellular functioning. The essential character of these stress proteins in promoting the survival of cells has contributed to them being remarkably well conserved across phyla, with nearly identical stress proteins being expressed in the simplest prokaryotic cells as well as the most complex eukaryotic ones. [3]

Stress proteins can exhibit widely varied functions within a cell- both during normal life processes and in response to stress. For example, studies in Drosophila have indicated that when DNA encoding certain stress proteins exhibit mutation defects, the resulting cells have impaired or lost abilities such as normal mitotic division and proteasome-mediated protein degradation. As expected, such cells were also highly vulnerable to stress, and ceased to be viable at elevated temperature ranges. [2]

Although stress response pathways are mediated in different ways depending on the stressor involved, cell type, etc., a general characteristic of many pathways – especially ones where heat is the principal stressor – is that they are initiated by the presence and detection of denatured proteins. Because conditions such as high temperatures often cause proteins to denature, this mechanism enables cells to determine when they are subject to high temperature without the need of specialized thermosensitive proteins.[ citation needed ] Indeed, if a cell under normal (meaning unstressed) conditions has denatured proteins artificially injected into it, it will trigger a stress response.

Response to heat

Cells subjected to heat shock. Cells in slide 'e' exhibit dysmorphic nuclei as a result of this exposure to stress, however 24 hours later cells largely recovered, as shown in slide 'f'. Confocal analysis of dermal fibroblasts after heat shock stress (progeria) CROPPED.jpg
Cells subjected to heat shock. Cells in slide 'e' exhibit dysmorphic nuclei as a result of this exposure to stress, however 24 hours later cells largely recovered, as shown in slide 'f'.

The heat shock response involves a class of stress proteins called heat shock proteins. [4] [5] These can help defend a cell against damage by acting as 'chaperons' in protein folding, ensuring that proteins assume their necessary shape and do not become denatured. [6] This role is especially crucial since elevated temperature would, on its own, increase the concentrations of malformed proteins. Heat shock proteins can also participate in marking malformed proteins for degradation via ubiquitin tags. [7]

Response to toxins

Many toxins end up activating similar stress proteins to heat or other stress-induced pathways because it is fairly common for some types of toxins to achieve their effects - at least in part - by denaturing vital cellular proteins. For example, many heavy metals can react with sulfhydryl groups stabilizing proteins, resulting in conformational changes. [3] Other toxins that either directly or indirectly lead to the release of free radicals can generate misfolded proteins. [3]

Effects on cancer

Cell stress can have both cancer-suppressing and cancer-promoting effects. Increased levels of oxidant stress may kill cancer cells. [8] Furthermore, different forms of cellular stress can cause protein misfolding and aggregation leading to proteotoxicity. [9] Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which trigger autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. [10] There are links between unfolded protein response (UPR) responses and autophagy, oxidative stress, and inflammatory response signals in ER stress: aggregation of unfolded/misfolded proteins in the endoplasmic reticulum lumen causes the UPR to be activated. Chronic ER stress produces endogenous or exogenous damage to cells and activates UPR, which leads to impaired intracellular calcium and redox homeostasis. [11] Cancer cells may become dependent on stress response mechanisms that involve lysosomal macromolecule degradation, or even autophagy that recycles entire organelles [12] However, tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins. [13] Furthermore, cancer cells with aberrant regulatory modifications in the chromatin of certain genes respond with different kinetics to cell stress, triggering expression of genes that protect them from cytotoxic conditions, and also by activating expression of genes that influence surrounding tissue in a manner that facilitates tumor growth. [14]

Applications

Early research has suggested that cells which are better able to synthesize stress proteins and do so at the appropriate time are better able to withstand damage caused by ischemia and reperfusion. [15] In addition, many stress proteins overlap with immune proteins. These similarities have medical applications in terms of studying the structure and functions of both immune proteins and stress proteins, as well as the role each plays in combating disease. [2]

See also

Related Research Articles

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.

<span class="mw-page-title-main">Hsp70</span> Family of heat shock proteins

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. 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 stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

<span class="mw-page-title-main">Autophagy</span> Process of cells digesting parts of themselves

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">Clusterin</span> Protein-coding gene in the species Homo sapiens

In humans, clusterin (CLU) is encoded by the CLU gene on chromosome 8. CLU is an extracellular molecular chaperone which binds to misfolded proteins in body fluids to neutralise their toxicity and mediate their cellular uptake by receptor-mediated endocytosis. Once internalised by cells, complexes between CLU and misfolded proteins are trafficked to lysosomes where they are degraded. CLU is involved in many diseases including neurodegenerative diseases, cancers, inflammatory diseases, and aging.

<span class="mw-page-title-main">Heat shock response</span> Type of cellular stress response

The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal cell, proteostasis must be maintained because proteins are the main functional units of the cell. Many proteins take on a defined configuration in a process known as protein folding in order to perform their biological functions. If these structures are altered, critical processes could be affected, leading to cell damage or death. The heat shock response can be employed under stress to induce the expression of heat shock proteins (HSP), many of which are molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.

<span class="mw-page-title-main">HSPA8</span> Protein-coding gene in the species Homo sapiens

Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.

In eukaryotic cells, an aggresome refers to an aggregation of misfolded proteins in the cell, formed when the protein degradation system of the cell is overwhelmed. Aggresome formation is a highly regulated process that possibly serves to organize misfolded proteins into a single location.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.

<span class="mw-page-title-main">Heat shock factor</span> Transcription factor

In molecular biology, heat shock factors (HSF), are the transcription factors that regulate the expression of the heat shock proteins. A typical example is the heat shock factor of Drosophila melanogaster.

<span class="mw-page-title-main">Heat shock factor protein 1</span> Protein-coding gene in the species Homo sapiens

Heat shock factor protein 1 is a protein that in humans is encoded by the HSF1 gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.

<span class="mw-page-title-main">MAPKAPK2</span> Protein-coding gene in the species Homo sapiens

MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene.

<span class="mw-page-title-main">Binding immunoglobulin protein</span> Protein-coding gene in the species Homo sapiens

Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.

<span class="mw-page-title-main">ERN1</span> Protein-coding gene in the species Homo sapiens

The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.

<span class="mw-page-title-main">Protein aggregation</span> Accumulation of clumps of misfolded or disordered proteins

In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.

Richard I. Morimoto is a Japanese American molecular biologist. He is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research at Northwestern University.

Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies.

Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

The mitochondrial unfolded protein response (UPRmt) is a cellular stress response related to the mitochondria. The UPRmt results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them. The UPRmt can occur either in the mitochondrial matrix or in the mitochondrial inner membrane. In the UPRmt, the mitochondrion will either upregulate chaperone proteins or invoke proteases to degrade proteins that fail to fold properly. UPRmt causes the sirtuin SIRT3 to activate antioxidant enzymes and mitophagy.

References

  1. ↑ Nakagawa K, Lokugamage KG, Makino S (2016-01-01). Ziebuhr J (ed.). "Viral and Cellular mRNA Translation in Coronavirus-Infected Cells". Advances in Virus Research. Coronaviruses. 96. Academic Press: 165–192. doi:10.1016/bs.aivir.2016.08.001. ISBN   9780128047361. PMC   5388242 . PMID   27712623.
  2. 1 2 3 Welch WJ (May 1993). "How cells respond to stress". Scientific American. 268 (5): 56–64. doi:10.1038/scientificamerican0593-56. PMID   8097593.
  3. 1 2 3 The Cell Stress Response (Report). Simon Fraser University.
  4. ↑ Hofer H, East ML (1998-01-01). "Biological Conservation and Stress". In Møller AP, Milinski M, Slater PJ (eds.). Stress and Behavior. Advances in the Study of Behavior. Vol. 27. Academic Press. pp. 405–525. doi:10.1016/s0065-3454(08)60370-8. ISBN   9780120045273.
  5. ↑ Bignold LP (2015-01-01). "Chapter 10 - Sublethal Injuries and Deaths of Cells and Tissues". In Bignold LP (ed.). Principles of Tumors. Boston: Academic Press. pp. 265–285. doi:10.1016/b978-0-12-801565-0.00010-x. ISBN   9780128015650.
  6. ↑ Richter K, Haslbeck M, Buchner J (October 2010). "The heat shock response: life on the verge of death". Molecular Cell. 40 (2): 253–66. doi: 10.1016/j.molcel.2010.10.006 . PMID   20965420.
  7. ↑ Rodríguez-Vargas JM, Oliver FJ (2016-01-01). "Chapter 3 - Role of Poly(ADP-Ribose)". In Hayat MA (ed.). Catalyzing Starvation-Induced Autophagy. Academic Press. pp. 99–118. doi:10.1016/b978-0-12-805421-5.00003-3. ISBN   978-0-12-805421-5.{{cite book}}: |work= ignored (help)
  8. ↑ Nakamura H, Takada K (October 2021). "Reactive oxygen species in cancer: Current findings and future directions". Cancer Sci. 112 (10): 3945–3952. doi:10.1111/cas.15068. PMC   8486193 . PMID   34286881.
  9. ↑ McConkey DJ (Jan 2017). "The integrated stress response and proteotoxicity in cancer therapy". Biochem Biophys Res Commun. 482 (3): 450–453. doi:10.1016/j.bbrc.2016.11.047. PMC   5319732 . PMID   28212730.
  10. ↑ Alam R, Kabir MF, Kim HR, Chae HJ (Nov 2022). "Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy". Cells. 11 (23): 3373. doi: 10.3390/cells11233773 . PMC   9738281 . PMID   36497032.
  11. ↑ Lin Y, Jiang M, Chen W, Zhao T, Wei Y (October 2019). "Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response". Biomed Pharmacother. 118: 109249. doi: 10.1016/j.biopha.2019.109249 . PMID   31351428.
  12. ↑ Varisli L, Cen O, Vlahopoulos S (March 2020). "Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways". Immunology. 159 (3): 257–278. doi:10.1111/imm.13160. PMC   7011648 . PMID   31782148.
  13. ↑ Eguchi T, Sogawa C, Ono K, Matsumoto M, Tran MT, Okusha Y, Lang BJ, Okamoto K, Calderwood SK (Mar 2020). "Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells". Cells. 9 (3): 755. doi: 10.3390/cells9030755 . PMC   7140686 . PMID   32204513.
  14. ↑ Vlahopoulos, SA (2024). "Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin". International Journal of Molecular Sciences. 25 (16): 8621. doi: 10.3390/ijms25168621 . PMC   11354898 . PMID   39201306.
  15. ↑ Majmundar AJ, Wong WJ, Simon MC (October 2010). "Hypoxia-inducible factors and the response to hypoxic stress". Molecular Cell. 40 (2): 294–309. doi:10.1016/j.molcel.2010.09.022. PMC   3143508 . PMID   20965423.
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