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Heat Shock Proteins Unveiled: Learn about these molecular chaperones' vital role in cellular health, stress response, and their potential implications for various medical conditions.
What are Heat Shock Proteins?
Heat shock proteins (HSP) are a group of proteins found in almost all living organisms, from bacteria to humans. This fact suggests that these proteins have evolved early on and have significant roles in most beings.
They are produced in response to the exposure of cells to stressful conditions. These stressful conditions have primarily been understood to be heat shock.
Still, we know that heat shock proteins are also produced during exposure to cold and UV light and when a wound is healing or tissue remodeling is present.
Heat shock proteins are divided into molecular weight, structure and function into five major families; HSP100, 90, 70, 60 and small heat shock proteins (sHsp). Each number refers to the protein's respective weight in kilodaltons.
The small protein ubiquitin is small in size at eight kilodaltons and has heat shock protein features, marking proteins for degradation.
An sHsp has a roughly 80 amino acid alpha-crystallin domain. sHsp have been found to act as low molecular weight chaperones, help regulate cytoskeleton assembly, and are associated with myofibrils.
The more common stress proteins can increase to high levels of heat shock protein cells, but they can also exist at low to moderate levels in cells that have not been exposed to stress, demonstrating that they play a role in normal cells.
In most mammals, Hsp90 and Hsp60 are bountiful at normal temperatures, yet heat shock protein 70 (Hsp70) is barely detectable but is further induced by stress.
In Escherichia coli, for example, at normal temperatures, Hsp6p and Hsp70 make up 1.5% of total cell protein yet makeup 30% after heat shock. This kind of HSP has been shown to enhance the expression of intracellular cell adhesion molecules and vascular cell adhesion molecules.
Certain heat shock proteins function as a chaperone by stabilizing new proteins as they are created by ensuring they correctly fold or refold proteins damaged by heat stress. This process is transcriptionally regulated, where a segment of DNA is copied into RNA.
Heat shock proteins are upregulated, a process by which the cell dramatically increases the quantity of a cellular component, like RNA or protein, after undergoing an external stimulus.
This upregulation is crucial to the heat shock response and is induced by the transcription factors called heat shock factors (HSF).
Discovery
Heat shock proteins were first discovered by accident in 1962 by Italian geneticist Ferruccio Ritossa.
They were called heat shock proteins due to their increased synthesis post-heat shock in the fruit flies that Ritossa studied.
He noted that heat and the metabolic uncoupler 2,4-dinitrophenol caused a particular pattern of "puffing" in the chromosomes in the fruit flies suffering from heat shock.
This puffing expressed heat shock proteins, also called stress proteins. In 1974, Alfred Tissieres, Herschel Mitchell and Ursula Tracy discovered that heat shock encourages the production of a certain smaller number of proteins and suppresses the production of a larger amount of proteins.
This finding jump-started a larger number of studies on these biochemical findings on the induction of heat shock and its role.
The Function of Heat Shock Proteins
Heat shock proteins have a few different roles. Five significant roles are important to understand—upregulation in stress, role as a chaperone, management of proteins, cardiovascular health, and immunity.
Upregulation in Stress
The production of large amounts of high heat shock proteins, also known as stress proteins, are triggered by environmental and metabolic stresses like:
- Infection
- Inflammation
- Exercise
- UV light
- Starvation
- Lack of oxygen or water (hypoxia)
- Nitrogen deficiency in plants
- Exposure to harmful materials like ethanol, arsenic, trace metals, ethanol, nicotine
- Surgical stress and viral agents
This upregulation of heat shock proteins during environmental stresses is part of the stress response.
During these environmental stresses, outer membrane proteins cannot fold and fit correctly into the outer membrane and, therefore, accumulate in the periplasmic space where the outer membrane proteins are detected by an inner membrane protease, which passes the signal through the membrane onto the sigmaE transcription factor.
Sigma factors are subunits of RNA polymerase that hold critical roles in the transcription initiation, which help with the initial steps of RNA synthesis.
Yet, some researchers are finding that heat shock proteins are recruited when there is an increase in damaged or abnormal proteins.
Certain bacterial heat shock proteins undergo this upregulation process by recruiting a mechanism involving RNA thermometers. These RNA thermometers regulate gene expression during heat shock and cold shock responses.
An important discovery was made by researchers who found that when a "mild heat shock pretreatment" was applied in fruit flies, it induced heat shock gene expression, mainly affecting the translation of the messenger RNA and not the transcription of RNA.
This process significantly enhanced their survival after a higher temperature heat shock.
In reverse, heat shock proteins were also synthesized in fruit flies when exposed to prolonged cold exposure rather than heat shock.
This result is significant as it shows that when exposed to a mild heat shock pretreatment, there are successive benefits in preventing damage and death when exposed to a following heat shock and exposure to cold.
Role as Molecular Chaperones
Certain heat shock proteins also act as intracellular molecular chaperones for other proteins, playing a central role in the interactions between protein folding, ensuring the appropriate protein conformation, and preventing protein aggregation.
Heat shock proteins act as stabilizers in unfolding misfolded proteins and help transport proteins across cell membranes.
Since this role as a molecular chaperone is crucial in maintaining proteins, heat shock proteins have been found in almost all organisms at low levels.
Management
When heat shock proteins are not exposed to environmental stressors, they act as "monitors" by monitoring the proteins of cells.
The monitoring process is part of the cell's repair system, called the cellular stress response or heat shock response; it consists of transporting old proteins to the cell's proteasome and helping newly synthesized proteins fold correctly.
Heat shock proteins seem more prone to self-degradation when compared to other proteins because of their proteolytic action, which is the breakdown of proteins into polypeptides or amino acids during oxidative stress, proteolytic aggression, or inflammation.
Cardiovascular
The role that heat shock proteins play in cardiovascular is significant, with Hsp90, Hsp84, Hsp70, Hsp27, Hsp20, and ɑB crystallin all playing an important role in cardiovascular.
These roles include binding endothelial nitric oxide synthase and guanylate cyclase, which are involved in vascular relaxation, managing oxidative stress and physiological factors and regulating cardiac morphogenesis. HSPs also play a role in:
- Developing smooth muscle phenotype (type of muscle in the respiratory, urinary, GI and reproductive systems)
- Preventing platelet aggregation
- Cardiac myocyte function
- Prevention of apoptosis after an ischemic injury
- Skeletal muscle function
- Muscle insulin response
Heat shock proteins may also be potential therapeutic targets to strengthen vascular defences and delay or avoid clinical complications that come from atherothrombosis - a cardiovascular disease.
Immunity
Heat shock proteins play a role in immunity because they bind to whole proteins and peptides. This interaction, however, is rare with mainly Hsp70, Hsp90, and gp96 and their peptide-binding sites containing this ability.
Additionally, heat shock proteins stimulate the immune receptors and their role in the correct folding of proteins involved in the pro-inflammatory signaling pathways.
Medical Significance
Heat Shock Factor 1 (HSF-1)
HSF-1 is a transcription factor that plays a role in maintaining and upregulating the Hsp70 expression, which researchers have discovered to be a multifaceted modifier of carcinogenesis. Carcinogenesis is the process by which normal cells are transformed into cancerous cells.
In a study of HSF-1 knockout mice where researchers applied a topical mutagen (a chemical agent that permanently damages genetic material) of DMBA, the HSF-1 mice had a decreased rate of skin tumors.
Additionally, it has been found that HSF-1 inhibition by an RNA aptamer attenuates mitogenic signaling and starts apoptosis, the program of cell death of cancer cells.
Diabetes Mellitus
Diabetes mellitus is an immune disease with excess glucose (hyperglycemia), usually brought on by an insulin deficiency. New research suggests a correlation between Hsp70, Hsp60 and diabetes mellitus.
Some research shows that the ratio of eHsp70 and iHsp70 could affect diabetes mellitus, indicating that eHsp70 and iHsp70 are biomarkers for patients' glycemic and inflammatory statuses.
Furthermore, a study looked at Hsp70 in blood serum in patients with diabetes vs control patients (no diabetes) and found that those patients with diabetes had significantly higher levels of Hsp70 and even higher in patients who had diabetes for more than five years than those newly diagnosed.
This finding suggests that the levels of Hsp70 in blood serum indicate metabolic derangement in the course of diabetes.
Cancer
Heat shock proteins have the potential to play a crucial role when it comes to the identification of cancer. High expression of extracellular heat shock proteins has been shown to indicate highly aggressive tumor cells.
Also, it correlates with cell proliferation, cancer stage and poor clinical outcomes, which indicates the potential use of heat shock protein expression in the process of a cancer diagnosis. Oncologists have even started using heat shock proteins to diagnose oral cancer.
Techniques such as dot immunoassay and ELISA have shown potential in cancer diagnosis. Researchers have determined that HSP-specific phage antibodies are beneficial in test tube (in-vitro) cancer diagnosis.
Heat shock proteins have also been shown to interact with cancer adaptations like drug resistance, tumor cell production and lifespan. The up-regulation and down-regulation of the microRNA associated with cancer are called oncomirs.
Hsp90 is one of the more promising candidates for the diagnosis, prognosis and treatment of cancer and Hsp70, Hsp60, and small HSP have been shown to have potential benefits for treating:
- Neurodegenerative disease
- Ischemia
- Cell death
- Autoimmunity
- Graft rejection
- Other critical diseases
Pharmaceutical Applications
Cancer Vaccines
Heat shock proteins act efficiently as immunologic adjuvants, which can increase the immune response to a vaccine.
Additionally, some studies suggest that heat shock proteins might be involved in binding the protein fragments of dead and malignant cells, such as cancerous cells and bringing them to the immune system to fight off.
Heat shock proteins have also been found to impact the signaling pathways that are part of the formation of cancer cells or carcinogenesis. Ultimately, heat shock proteins can potentially increase the effectiveness of vaccines against cancer. Isolated heat shock proteins from tumor cells can act as an anti-tumor vaccine.
Since tumor cells are under continual stress and need to chaperone large numbers of mutated oncogenes or cancer-causing genes, they create an exceptional amount of heat shock proteins within the tumor cells.
When isolated from the tumor, these particular heat shock proteins have a peptide repertoire that acts as a map or fingerprint of the tumor cells they came from.
These heat shock proteins have the potential to be applied back to the patient to help fight against the tumor with the goal of tumor regression.
Anticancer Therapeutics
Heat shock proteins are heavily expressed intracellularly in cancerous cells. They are critical for the survival of cancerous cells, even promoting more invasive cells or the metastasis formation of tumors.
Because of this, small molecule inhibitors of heat shock proteins such as Hsp90 have the potential to be an anticancer therapeutic. Researchers are studying these potential therapeutics. However, clinical trials have yet to pass.
Autoimmunity Treatment
Heat shock proteins can act as damage-associated molecular patterns, molecules in cells that are a part of the innate immune response released from cells dying from trauma or infection. Therefore, heat shock proteins can extracellularly encourage certain autoimmune diseases.
However, it has been found that heat shock proteins can be used in patients with autoimmune diseases to induce immune tolerance and help treat these diseases.
Hsp90 inhibitors also have the potential for treating autoimmune diseases with their role in the correct folding of pro-inflammatory proteins. Diseases like rheumatoid arthritis and type 1 diabetes can be treated through autoimmunity treatments.
At Home Applications
Heat Exposure
Deliberate heat exposure, especially sauna use, can play a beneficial role in maintaining good health and has benefits ranging from cardiovascular health to releasing growth hormones.
Sauna used 2-3x per week, up to 7x per week from 5-20 minutes per session at around 80-100℃ (176-212℉) can benefit cardiovascular health, improve mood by releasing dynorphins and endorphins, and improve stress responses.
Heat exposure is a form of hormesis, a mild, tolerable stress on the body that results in a positive adaptation.
Using a sauna can decrease cortisol or stress levels and encourage the activation of DNA repair and longevity pathways, increasing heat shock proteins.
The thermal stress created in the body from sauna use, upregulates heavy shock proteins intracellularly, preventing protein aggregation, helping to transport repair proteins and enhancing the immune system.
Heat stress has huge benefits to overall health for all people. Studies show that timely heat stress might bring benefits more typically found in exercise for those unable to exercise to the extent recommended due to age, injury and/or chronic disease.
Cold Exposure
Deliberate cold exposure also has benefits for heat shock proteins. A study on cold exposure found that cold temperatures resulted in the tissue-selective introduction of heat shock proteins in brown adipose tissue, which has significant metabolic benefits.
This cold-induced heat shock protein expression has specific benefits in that there is an enhanced binding of their transcription factors to DNA.
Takeaway
In conclusion, the world of heat shock proteins (HSPs) is proving to be a promising avenue in our quest to better understand and combat neurodegenerative diseases.
These stress proteins, tasked with refolding denatured proteins and maintaining cellular equilibrium, offer potential breakthroughs in developing therapies.
As we unravel the intricate biology web, targeting heat shock proteins could hold the key to addressing the complexities of neurodegenerative diseases, offering hope for improved treatments and a brighter future.
References
Bacterial Sigma Factors and Anti-Sigma Factors: Structure, Function and Distribution - PMC.
Deliberate Heat Exposure Protocols for Health & Performance - Huberman Lab
Extracellular heat shock proteins and cancer: New perspectives - PMC
Heat Shock Protein - an overview | ScienceDirect Topics
Heat-shock proteins: chaperoning DNA repair | Oncogene.
Heat shock proteins: a therapeutic target worth to consider - PMC.
Heat shock proteins: A review of the molecular chaperones - ScienceDirect
Heat shock protein - Wikipedia
Increased serum HSP70 levels are associated with the duration of diabetes - PMC
Stress (Heat Shock) Proteins | Circulation Research
Transcription (biology) - Wikipedia
Disclaimer
The contents of this article are provided for informational purposes only and are not intended to substitute for professional medical advice, diagnosis, or treatment. It is always recommended to consult with a qualified healthcare provider before making any health-related changes or if you have any questions or concerns about your health. Anahana is not liable for any errors, omissions, or consequences that may occur from using the information provided.
By: Clint Johnson
Clint is the driving force and founder of Anahana. Clint teaches Yoga, Pilates, mindful breathing, and meditation, catering to a global community of students and teachers.