Heat shock response: Difference between revisions
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'''Heat shock''' is a cellular response that increases the number of molecular chaperones to combat the negative proteomic effects caused by stressors such as augmented temperatures, oxidative stress, and heavy metals.<ref name="pmid8451637">{{cite journal | |
'''Heat shock''' is a cellular response that increases the number of molecular chaperones to combat the negative proteomic effects caused by stressors such as augmented temperatures, oxidative stress, and heavy metals.<ref name="pmid8451637">{{cite journal |doi=10.1126/science.8451637 }}</ref> In a normal cell, protein homeostasis (proteostasis) must be maintained because proteins are the main functional units of the cell.<ref>{{cite journal |doi=10.1126/science.aac4354 }}</ref> Proteins take on a defined configuration in order to gain functionality. If these structures are altered, critical processes could be affected, leading to cell damage or death.<ref name="pmid20965420">{{cite journal |doi=10.1016/j.molcel.2010.10.006 }}</ref> With the importance of proteins established, the heat shock response (HSR) can be employed under stress to induce heat shock proteins (HSP), also known as molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.<ref name=":0">{{cite journal |doi=10.1515/BC.2005.086 }}</ref> |
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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.<ref name=":1"> |
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.<ref name=":1">{{cite journal |doi=10.1152/physrev.1999.79.2.425 }}</ref> If the work by molecular chaperones is not enough to prevent incorrect folding, the protein may be degraded by the proteasome or autophagy to remove any potentially toxic aggregates.<ref>{{cite journal |doi=10.1038/cr.2013.153 }}</ref> 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.<ref name=":2">{{cite journal |doi=10.1016/j.tem.2008.12.005 }}</ref> Heat shock proteins induced by the HSR can help prevent protein aggregation that can lead to common neurodegenerative diseases such as [[Alzheimer's disease|Alzheimer's]], [[Huntington's disease|Huntington's]], or [[Parkinson's disease|Parkinson's Disease]].<ref>{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK6495/ |title=The Role of Heat Shock Proteins during Neurodegeneration in Alzheimer's, Parkinson's and Huntington's Disease |last=Wyttenbach |first=Andreas |last2=Arrigo |first2=André Patrick |date=2013 |publisher=Landes Bioscience |language=en }}</ref> |
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[[File:Heat Shock Response Pathway.tif|thumb|The diagram depicts actions taken when a stress is introduced to the cell. Stress will induce HSF-1 and cause proteins to misfold. Molecular chaperones will aid these proteins to fold correctly or if the degree of misfolding is too severe, the protein will be eliminated through the proteasome or autophagy.]] |
[[File:Heat Shock Response Pathway.tif|thumb|The diagram depicts actions taken when a stress is introduced to the cell. Stress will induce HSF-1 and cause proteins to misfold. Molecular chaperones will aid these proteins to fold correctly or if the degree of misfolding is too severe, the protein will be eliminated through the proteasome or autophagy.]] |
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== Induction of the heat shock response == |
== 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.<ref> |
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.<ref>{{cite journal |doi=10.1038/nm.4001 }}</ref> HSPs (e.g. HSP70, HSP90, HSP60, etc.) are present under normal conditions but under heat stress, they are upregulated by the transcription factor heat shock factor 1 (HSF-1).<ref>{{cite journal |pmid=1628823 |url=http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=1628823 }}</ref><ref name="pmid9493008">{{cite journal |pmid=9493008 }}</ref> There are four different transcription factors found in vertebrates (HSF 1-4) where the main regulator of HSPs is HSF-1, while σ<sup>32</sup> is the heat shock transcription factor in ''Escherichia coli.''<ref>{{cite journal |doi=10.1196/annals.1391.005 }}</ref><ref name="pmid18772288">{{cite journal |doi=10.1128/MMBR.00007-08 }}</ref> When not bound to DNA, HSF-1 is in a monomeric state where it is inactive and negatively regulated by chaperones.<ref name=":3">{{cite journal |doi=10.1091/mbc.e03-07-0532 }}</ref> When a stress occurs, these chaperones are released due to the presence of denatured proteins and various conformational changes to HSF-1 cause it to undergo nuclear localization where it becomes active through trimerization.<ref>{{cite journal |doi=10.1007/s00018-018-2836-6 }}</ref><ref name=":3" /> Newly trimerized HSF-1 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.<ref>{{cite journal |doi=10.1196/annals.1391.005 }}</ref> HSF-1 will also regulate expression of HSPs through epigenetic modifications. The HSR will eventually attenuate as HSF-1 returns to its monomeric form, negatively regulated through association with HSP70 and HSP90 along with additional post-translational modifications.<ref>{{cite journal |doi=10.1091/mbc.e03-10-0738 }}</ref> 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.<ref name=":4">{{cite journal |doi=10.1016/j.cell.2014.05.039 }}</ref> |
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==Molecular chaperones== |
==Molecular chaperones== |
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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.<ref name="pmid2853609">{{cite journal |
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.<ref name="pmid2853609">{{cite journal |doi=10.1146/annurev.ge.22.120188.003215 }}</ref> Chaperones bind to their substrate (i.e. a misfolded protein) in an ATP-dependent manner to perform a specific function.<ref>{{cite journal |doi=10.1016/j.febslet.2013.05.014 }}</ref> Exposed hydrophobic residues are a major problem with regards to protein aggregation because they can interact with one another and form hydrophobic interactions.<ref name=":5">{{cite journal |doi=10.1101/cshperspect.a004390 }}</ref> It is the job of chaperones to prevent this aggregation by binding to the residues or providing proteins a “safe” environment to fold properly.<ref>{{cite journal |pmid=11573347 }}</ref> Heat shock proteins are also believed to play a role in the presentation of pieces of proteins (or [[Peptide|peptides]]) on the cell surface to help the [[immune system]] recognize diseased cells.<ref name="tsan">{{cite journal |doi=10.1189/jlb.0109005 }}</ref> The major HSPs involved in the HSR include HSP70, HSP90, and HSP60.<ref name=":1" /> Chaperones include the HSP70s and HSP90s while HSP60s are considered to be chaperonins.<ref name=":4" /> |
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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.<ref name=":6"> |
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.<ref name=":6">{{cite journal |doi=10.1038/nature10317 }}</ref> 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.<ref name=":7">{{cite journal |doi=10.3389/fnins.2017.00254 }}</ref> 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.<ref>{{cite journal |doi=10.1007/s00018-004-4464-6 }}</ref> 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.<ref>{{cite journal |doi=10.1159/000225957 }}</ref> 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.<ref>{{cite journal |doi=10.1080/15548627.2015.1009776 }}</ref> HSP90s are parallel to HSP70s with respect to the refolding or proteins and use in protein clearance.<ref name=":0" /> 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.<ref name=":7" /> |
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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.<ref name=":6" /> 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 .<ref name=":2" /> HSP60s are barrel shaped and suited to bind to the hydrophobic residues of proteins.<ref> |
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.<ref name=":6" /> 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 .<ref name=":2" /> HSP60s are barrel shaped and suited to bind to the hydrophobic residues of proteins.<ref>{{cite journal |doi=10.1073/pnas.0809794105 }}</ref> Once a cap binds to the chaperonin, the protein is free within the barrel to undergo hydrophobic collapse and reach a stable conformation.<ref>{{cite journal |doi=10.1021/ja203275f }}</ref> 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.<ref>{{cite journal |pmid=8633011 }}</ref> These chaperones function to remove aggregation and significantly speed up protein folding.<ref name=":5" /> |
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== See also == |
== See also == |
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Revision as of 13:51, 28 November 2018
Heat shock is a cellular response that increases the number of molecular chaperones to combat the negative proteomic effects caused by stressors such as augmented temperatures, oxidative stress, and heavy metals.[1] In a normal cell, protein homeostasis (proteostasis) must be maintained because proteins are the main functional units of the cell.[2] Proteins take on a defined configuration in order to gain functionality. If these structures are altered, critical processes could be affected, leading to cell damage or death.[3] With the importance of proteins established, the heat shock response (HSR) can be employed under stress to induce heat shock proteins (HSP), also known as molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.[4]
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.[5] If the work by molecular chaperones is not enough to prevent incorrect folding, the protein may be degraded by the proteasome or autophagy to remove any potentially toxic aggregates.[6] 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.[7] Heat shock proteins induced by the HSR can help prevent protein aggregation that can lead to common neurodegenerative diseases such as Alzheimer's, Huntington's, or Parkinson's Disease.[8]
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.[9] HSPs (e.g. HSP70, HSP90, HSP60, etc.) are present under normal conditions but under heat stress, they are upregulated by the transcription factor heat shock factor 1 (HSF-1).[10][11] There are four different transcription factors found in vertebrates (HSF 1-4) where the main regulator of HSPs is HSF-1, while σ32 is the heat shock transcription factor in Escherichia coli.[12][13] When not bound to DNA, HSF-1 is in a monomeric state where it is inactive and negatively regulated by chaperones.[14] When a stress occurs, these chaperones are released due to the presence of denatured proteins and various conformational changes to HSF-1 cause it to undergo nuclear localization where it becomes active through trimerization.[15][14] Newly trimerized HSF-1 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.[16] HSF-1 will also regulate expression of HSPs through epigenetic modifications. The HSR will eventually attenuate as HSF-1 returns to its monomeric form, negatively regulated through association with HSP70 and HSP90 along with additional post-translational modifications.[17] 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.[18]
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.[19] Chaperones bind to their substrate (i.e. a misfolded protein) in an ATP-dependent manner to perform a specific function.[20] Exposed hydrophobic residues are a major problem with regards to protein aggregation because they can interact with one another and form hydrophobic interactions.[21] It is the job of chaperones to prevent this aggregation by binding to the residues or providing proteins a “safe” environment to fold properly.[22] Heat shock proteins are also believed to play a role in the presentation of pieces of proteins (or peptides) on the cell surface to help the immune system recognize diseased cells.[23] The major HSPs involved in the HSR include HSP70, HSP90, and HSP60.[5] Chaperones include the HSP70s and HSP90s while HSP60s are considered to be chaperonins.[18]
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.[24] 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.[25] 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.[26] 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.[27] 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.[28] HSP90s are parallel to HSP70s with respect to the refolding or proteins and use in protein clearance.[4] 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.[25]
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.[24] 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 .[7] HSP60s are barrel shaped and suited to bind to the hydrophobic residues of proteins.[29] Once a cap binds to the chaperonin, the protein is free within the barrel to undergo hydrophobic collapse and reach a stable conformation.[30] 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.[31] These chaperones function to remove aggregation and significantly speed up protein folding.[21]
See also
References
- ^ . doi:10.1126/science.8451637.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1126/science.aac4354.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1016/j.molcel.2010.10.006.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1515/BC.2005.086.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1152/physrev.1999.79.2.425.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1038/cr.2013.153.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1016/j.tem.2008.12.005.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ Wyttenbach, Andreas; Arrigo, André Patrick (2013). The Role of Heat Shock Proteins during Neurodegeneration in Alzheimer's, Parkinson's and Huntington's Disease. Landes Bioscience.
- ^ . doi:10.1038/nm.4001.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . PMID 1628823 http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=1628823.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . PMID 9493008.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1196/annals.1391.005.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1128/MMBR.00007-08.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1091/mbc.e03-07-0532.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1007/s00018-018-2836-6.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1196/annals.1391.005.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1091/mbc.e03-10-0738.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1016/j.cell.2014.05.039.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1146/annurev.ge.22.120188.003215.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1016/j.febslet.2013.05.014.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1101/cshperspect.a004390.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . PMID 11573347.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1189/jlb.0109005.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.1038/nature10317.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b . doi:10.3389/fnins.2017.00254.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help)CS1 maint: unflagged free DOI (link) - ^ . doi:10.1007/s00018-004-4464-6.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1159/000225957.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1080/15548627.2015.1009776.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1073/pnas.0809794105.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1021/ja203275f.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . PMID 8633011.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help)