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The heat shock response (HSR) is a
cell stress response Cellular stress response is the wide range of molecular biology, molecular changes that cell (biology), cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage. Cellular stre ...
that increases the number of
molecular chaperone Chaperone proteins participate in the folding of over half of all mammalian proteins. In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between ...
s to combat the negative effects on
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s caused by stressors such as increased
temperature Temperature ( ) is a physical quantity that expresses hot and cold. It is the manifestation of thermal energy Thermal radiation in visible light can be seen on this hot metalwork. Thermal energy refers to several distinct physical concept ...

temperature
s,
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen ...
, and
heavy metals upright=1.2, Crystals of osmium, a heavy metal nearly twice as dense as lead">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 are generally defined as ...
. 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 Proteolysis, degradation of ...
(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 Physical changes are changes affecting the form of a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass ...

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
expression
of
heat shock protein Heat shock proteins (HSP) are a family of protein, proteins that are produced by cell (biology), cells in response to exposure to Stress (biology), stressful conditions. They were first described in relation to heat shock#Heat shock, heat shock, but ...
s (HSP), many of which are molecular chaperones, that help prevent or reverse
protein misfolding In medicine Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as facts ( descriptive knowledge), ...
and provide an environment for proper folding. Protein folding is already challenging due to the crowded intracellular space 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 protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēn ...

proteasome
or
autophagy Autophagy (or ''autophagocytosis'') (from the Ancient Greek Ancient Greek includes the forms of the used in and the from around 1500 BC to 300 BC. It is often roughly divided into the following periods: (), Dark Ages (), the perio ...

autophagy
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 Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane p ...
,
Huntington's Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane potentia ...
, or
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
.


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 #REDIRECT Hsp70#REDIRECT Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by mar ...

HSP70
,
HSP90 #REDIRECT hsp90#REDIRECT hsp90 of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively ...

HSP90
,
HSP60 HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 bel ...
, etc.) are present under normal conditions but under heat stress, they are upregulated by the
transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...
heat shock factor 1 (
HSF1 Heat shock factor 1 (HSF1) 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 Proteotoxicity, proteotoxic stress with important roles in no ...
). 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 region In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interacti ...
s 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
peptides Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
) on the cell surface to help the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
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.


Heat shock response and transcriptional downregulation

Upon heat shock, there is a second and less studied branch known as global transcriptional downregulation. Identified by John T Lis lab.


Discovery

Discovery of the heat shock response is attributed to Italian geneticist
Ferruccio Ritossa Ferruccio Ritossa (February 26, 1936 – January 9, 2014) was an Italian geneticist best known for his discovery of the heat shock response in the model organism ''Drosophila'' (fruit flies). Early life and education Ritossa was born in the tow ...
, who observed changes called chromosomal "puffs" in response to heat exposure while working with the
polytene chromosome Polytene chromosomes are large chromosomes which have thousands of DNA strands. They provide a high level of function in certain tissues such as salivary glands of insects Polytene chromosomes were first reported by Édouard-Gérard Balbiani, ...

polytene chromosome
s of ''
Drosophila ''Drosophila'' () is a genus of fly, flies, belonging to the family (biology), family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the character ...

Drosophila
''. By his own account, the discovery was the
serendipitous Serendipity is an unplanned fortunate discovery. Serendipity is a common occurrence throughout the history of product invention and scientific discovery. Serendipity is also seen as a potential design principle for online activities that would p ...
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 (HSP) are a family of protein, proteins that are produced by cell (biology), cells in response to exposure to Stress (biology), stressful conditions. They were first described in relation to heat shock#Heat shock, heat shock, but ...
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 responseThe bacterial stress response enables bacteria to survive adverse and fluctuating conditions in their immediate surroundings. Various bacterial mechanisms recognize different environmental changes and mount an appropriate response. A bacterial cell c ...


References

{{reflist Cellular processes