Heat Shock Response
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The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s caused by stressors such as increased
temperature Temperature is a physical quantity that quantitatively expresses the attribute of hotness or coldness. Temperature is measurement, measured with a thermometer. It reflects the average kinetic energy of the vibrating and colliding atoms making ...
s,
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, and
heavy metals upright=1.2, Crystals of lead.html" ;"title="osmium, a heavy metal nearly twice as dense as lead">osmium, a heavy metal nearly twice as dense as lead Heavy metals is a controversial and ambiguous term for metallic elements with relatively h ...
. In a normal cell,
proteostasis 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 prote ...
(protein homeostasis) 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 Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...
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 protein 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 ex ...
s (HSP), many of which are molecular chaperones, that help prevent or reverse
protein misfolding In medicine, proteinopathy ( 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain prote ...
and provide an environment for proper folding. Protein folding is already challenging due to the crowded
intracellular space Intracellular space is the interior space of the plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and prote ...
where aberrant interactions can arise; it becomes more difficult when environmental stressors can denature proteins and cause even more non-native folding to occur. If the work by molecular chaperones is not enough to prevent incorrect folding, the protein may be degraded by the
proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
or
autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
to remove any potentially toxic aggregates. Misfolded proteins, if left unchecked, can lead to aggregation that prevents the protein from moving into its proper conformation and eventually leads to plaque formation, which may be seen in various diseases. Heat shock proteins induced by the HSR can help prevent protein aggregation that is associated with common neurodegenerative diseases such as Alzheimer's, Huntington's, or
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
.


Induction of the heat shock response

With the introduction of environmental stressors, the cell must be able to maintain proteostasis. Acute or chronic subjection to these harmful conditions elicits a cytoprotective response to promote stability to the proteome. HSPs (e.g.
HSP70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms and play crucial roles in the development of can ...
,
HSP90 Hsp90 (heat shock protein 90) is a chaperone (protein), chaperone protein that assists other proteins to protein folding, fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of ...
, HSP60, etc.) are present under normal conditions but under heat stress, they are upregulated by the
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
heat shock factor 1 ( HSF1). There are four different transcription factors found in vertebrates (HSF 1–4) where the main regulator of HSPs is HSF1, while σ32 is the heat shock transcription factor in ''E. coli.'' When not bound to DNA, HSF1 is in a monomeric state where it is inactive and negatively regulated by chaperones. When a stress occurs, these chaperones are released due to the presence of denatured proteins and various conformational changes to HSF1 cause it to undergo nuclear localization where it becomes active through trimerization. Newly trimerized HSF1 will bind to heat shock elements (HSE) located in promoter regions of different HSPs to activate transcription of HSP mRNA. The mRNA will eventually be transcribed and comprise the upregulated HSPs that can alleviate the stress at hand and restore proteostasis. HSF1 will also regulate expression of HSPs through epigenetic modifications. The HSR will eventually attenuate as HSF1 returns to its monomeric form, negatively regulated through association with HSP70 and HSP90 along with additional post-translational modifications. The HSR is not only involved with increasing transcription levels of HSPs; other facets include stress-induced mRNA stability preventing errors in mRNA and enhanced control during translation to thwart misfolding.


Molecular chaperones

Molecular chaperones are typically referred to as proteins that associate with and help other proteins reach a native conformation while not being present in the end state. Chaperones bind to their substrate (i.e. a misfolded protein) in an ATP-dependent manner to perform a specific function. Exposed hydrophobic residues are a major problem with regards to protein aggregation because they can interact with one another and form hydrophobic interactions. It is the job of chaperones to prevent this aggregation by binding to the residues or providing proteins a "safe" environment to fold properly. Heat shock proteins are also believed to play a role in the presentation of pieces of proteins (or
peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
s) on the cell surface to help the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
recognize diseased cells. The major HSPs involved in the HSR include HSP70, HSP90, and HSP60. Chaperones include the HSP70s and HSP90s while HSP60s are considered to be chaperonins. The HSP70 chaperone family is the main HSP system within cells, playing a key role in translation, post-translation, prevention of aggregates and refolding of aggregated proteins. When a nascent protein is being translated, HSP70 is able to associate with the hydrophobic regions of the protein to prevent faulty interactions until translation is complete. Post-translational protein folding occurs in a cycle where the protein becomes bound/released from the chaperone allowing burying hydrophobic groups and aiding in overcoming the energy needed to fold in a timely fashion. HSP70 plays a part in de-aggregating proteins using the aforementioned mechanism; the chaperone will bind to exposed hydrophobic residues and either partially or fully disassemble the protein, allowing HSP70 to assist in the proper refolding. When proteins are beyond the point of refolding, HSP70s can help direct these potentially toxic aggregates to be degraded by the proteasome or through autophagy. HSP90s are parallel to HSP70s with respect to the refolding or proteins and use in protein clearance. One difference between the two HSPs is HSP90s ability to keep proteins in an unfolded yet stable configuration until a signal causes the protein to translocate and complete its folding. Sometimes, HSP70 is unable to effectively aid a protein in reaching its final 3-D structure; The main reason being the thermodynamic barriers for folding are too high for the chaperone to meet. Because the intracellular space is very crowded, sometimes proteins need an isolated space to prevent aberrant interactions between other proteins, which is provided by chaperonins or HSP60s . HSP60s are barrel shaped and suited to bind to the hydrophobic residues of proteins. Once a cap binds to the chaperonin, the protein is free within the barrel to undergo hydrophobic collapse and reach a stable conformation. Once the cap is removed, the protein can either be correctly folded and move on to perform its function or return to a HSP if it is still not folded accurately. These chaperones function to remove aggregation and significantly speed up protein folding.


Discovery

Discovery of the heat shock response is attributed to Italian geneticist Ferruccio Ritossa, who observed changes called chromosomal "puffs" in response to heat exposure while working with the polytene chromosomes of ''
Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
''. By his own account, the discovery was the serendipitous result of unintentional elevated temperature in a laboratory incubator. Ritossa's observations, reported in 1962, were later described as "the first known environmental stress acting directly on gene activity" but were not initially widely cited. The significance of these observations became clearer in the 1970s, as a distinct class of
heat shock protein 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 ex ...
s were discovered in the laboratory of Herschel K. Mitchell, and as heat shock responses were reported in other organisms and came to be recognized as universal.


See also

* Bacterial stress response


References

{{reflist Cellular processes