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 proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. [1] In a normal cell, proteostasis (protein homeostasis) must be maintained because proteins are the main functional units of the cell. [2] 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. [3] 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. [4]

Contents

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 is associated with common neurodegenerative diseases such as Alzheimer's, Huntington's, or Parkinson's disease. [8]

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. Heat Shock Response Pathway.tif
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.

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 (HSF1). [10] [11] 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. [12] [13] When not bound to DNA, HSF1 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 HSF1 cause it to undergo nuclear localization where it becomes active through trimerization. [15] [14] 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. [12] 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. [16] 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. [17]

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. [18] Chaperones bind to their substrate (i.e. a misfolded protein) in an ATP-dependent manner to perform a specific function. [19] Exposed hydrophobic residues are a major problem with regards to protein aggregation because they can interact with one another and form hydrophobic interactions. [20] It is the job of chaperones to prevent this aggregation by binding to the residues or providing proteins a "safe" environment to fold properly. [21] 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. [22] 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. [17]

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. [23] 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. [24] 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. [25] 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. [26] 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. [27] 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. [24]

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. [23] 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. [28] Once a cap binds to the chaperonin, the protein is free within the barrel to undergo hydrophobic collapse and reach a stable conformation. [29] 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. [30] These chaperones function to remove aggregation and significantly speed up protein folding. [20]

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 . [31] [32] By his own account, the discovery was the serendipitous result of unintentional elevated temperature in a laboratory incubator. [33] Ritossa's observations, reported in 1962, [34] were later described as "the first known environmental stress acting directly on gene activity" [31] but were not initially widely cited. [31] [35] The significance of these observations became clearer in the 1970s, as a distinct class of heat shock proteins were discovered in the laboratory of Herschel K. Mitchell, [36] and as heat shock responses were reported in other organisms and came to be recognized as universal. [31] [35] [37]

See also

References

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  2. ↑ Balchin D, Hayer-Hartl M, Hartl FU (July 2016). "In vivo aspects of protein folding and quality control". Science. 353 (6294) aac4354. doi:10.1126/science.aac4354. hdl: 11858/00-001M-0000-002B-0856-C . PMID   27365453. S2CID   5174431.
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  4. 1 2 Weibezahn J, Schlieker C, Tessarz P, Mogk A, Bukau B (August 2005). "Novel insights into the mechanism of chaperone-assisted protein disaggregation". Biological Chemistry. 386 (8): 739–44. doi:10.1515/BC.2005.086. PMID   16201868. S2CID   42852756.
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  9. ↑ Kaushik S, Cuervo AM (December 2015). "Proteostasis and aging". Nature Medicine. 21 (12): 1406–15. doi:10.1038/nm.4001. PMID   26646497. S2CID   3581766.
  10. ↑ Abravaya K, Myers MP, Murphy SP, Morimoto RI (July 1992). "The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression". Genes & Development. 6 (7): 1153–64. doi: 10.1101/gad.6.7.1153 . PMID   1628823.
  11. ↑ Morimoto RI, Kline MP, Bimston DN, Cotto JJ (1997). "The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones". Essays in Biochemistry. 32: 17–29. PMID   9493008.
  12. 1 2 Akerfelt M, Trouillet D, Mezger V, Sistonen L (October 2007). "Heat shock factors at a crossroad between stress and development". Annals of the New York Academy of Sciences. 1113 (1): 15–27. Bibcode:2007NYASA1113...15A. doi:10.1196/annals.1391.005. PMID   17483205. S2CID   10885427.
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  17. 1 2 Taipale M, Tucker G, Peng J, Krykbaeva I, Lin ZY, Larsen B, Choi H, Berger B, Gingras AC, Lindquist S (July 2014). "A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways". Cell. 158 (2): 434–448. doi:10.1016/j.cell.2014.05.039. PMC   4104544 . PMID   25036637.
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  19. ↑ Priya S, Sharma SK, Goloubinoff P (June 2013). "Molecular chaperones as enzymes that catalytically unfold misfolded polypeptides". FEBS Letters. 587 (13): 1981–7. doi: 10.1016/j.febslet.2013.05.014 . PMID   23684649.
  20. 1 2 Vabulas RM, Raychaudhuri S, Hayer-Hartl M, Hartl FU (December 2010). "Protein folding in the cytoplasm and the heat shock response". Cold Spring Harbor Perspectives in Biology. 2 (12) a004390. doi:10.1101/cshperspect.a004390. PMC   2982175 . PMID   21123396.
  21. ↑ Naylor DJ, Hartl FU (2001). "Contribution of molecular chaperones to protein folding in the cytoplasm of prokaryotic and eukaryotic cells". Biochemical Society Symposium. 68 (68): 45–68. doi:10.1042/bss0680045. PMID   11573347.
  22. ↑ Tsan MF, Gao B (June 2009). "Heat shock proteins and immune system". Journal of Leukocyte Biology. 85 (6): 905–10. doi: 10.1189/jlb.0109005 . PMID   19276179. S2CID   28474514.
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  24. 1 2 Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, Prado VF, Prado MA (2017). "The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases". Frontiers in Neuroscience. 11: 254. doi: 10.3389/fnins.2017.00254 . PMC   5433227 . PMID   28559789.
  25. ↑ Mayer MP, Bukau B (March 2005). "Hsp70 chaperones: cellular functions and molecular mechanism". Cellular and Molecular Life Sciences. 62 (6): 670–84. doi:10.1007/s00018-004-4464-6. PMC   2773841 . PMID   15770419.
  26. ↑ Calderwood SK, Murshid A, Prince T (2009). "The shock of aging: molecular chaperones and the heat shock response in longevity and aging--a mini-review". Gerontology. 55 (5): 550–8. doi:10.1159/000225957. PMC   2754743 . PMID   19546513.
  27. ↑ Dokladny K, Myers OB, Moseley PL (2015). "Heat shock response and autophagy--cooperation and control". Autophagy. 11 (2): 200–13. doi:10.1080/15548627.2015.1009776. PMC   4502786 . PMID   25714619.
  28. ↑ Apetri AC, Horwich AL (November 2008). "Chaperonin chamber accelerates protein folding through passive action of preventing aggregation". Proceedings of the National Academy of Sciences of the United States of America. 105 (45): 17351–5. Bibcode:2008PNAS..10517351A. doi: 10.1073/pnas.0809794105 . PMC   2579888 . PMID   18987317.
  29. ↑ Kmiecik S, Kolinski A (July 2011). "Simulation of chaperonin effect on protein folding: a shift from nucleation-condensation to framework mechanism". Journal of the American Chemical Society. 133 (26): 10283–9. doi:10.1021/ja203275f. PMC   3132998 . PMID   21618995.
  30. ↑ Todd MJ, Lorimer GH, Thirumalai D (April 1996). "Chaperonin-facilitated protein folding: optimization of rate and yield by an iterative annealing mechanism". Proceedings of the National Academy of Sciences of the United States of America. 93 (9): 4030–5. Bibcode:1996PNAS...93.4030T. doi: 10.1073/pnas.93.9.4030 . PMC   39481 . PMID   8633011.
  31. 1 2 3 4 Capocci, Mauro; Santoro, M. Gabriella; Hightower, Lawrence E. (September 2014). "The life and times of Ferruccio Ritossa". Cell Stress and Chaperones. 19 (5): 599–604. doi: 10.1007/s12192-014-0525-4 . PMC   4147064 . PMID   25142515.
  32. ↑ Majno, Guido; Joris, Isabelle (2004). Cells, tissues, and disease: principles of general pathology (2nd ed.). New York: Oxford University Press. p. 187. ISBN   978-0-19-974892-1.
  33. ↑ Ritossa, F (June 1996). "Discovery of the heat shock response". Cell Stress & Chaperones. 1 (2): 97–8. PMC   248460 . PMID   9222594.
  34. ↑ Ritossa, F. (December 1962). "A new puffing pattern induced by temperature shock and DNP in drosophila". Experientia. 18 (12): 571–573. doi:10.1007/BF02172188. S2CID   32525462.
  35. 1 2 De Maio, Antonio; Santoro, M. Gabriella; Tanguay, Robert M.; Hightower, Lawrence E. (March 2012). "Ferruccio Ritossa's scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal". Cell Stress and Chaperones. 17 (2): 139–143. doi: 10.1007/s12192-012-0320-z . PMC   3273555 . PMID   22252402.
  36. ↑ Tissiéres, Alfred; Mitchell, Herschel K.; Tracy, Ursula M. (April 1974). "Protein synthesis in salivary glands of Drosophila melanogaster: Relation to chromosome puffs". Journal of Molecular Biology. 84 (3): 389–398. doi:10.1016/0022-2836(74)90447-1. PMID   4219221.
  37. ↑ Schlesinger, MJ (25 July 1990). "Heat shock proteins". The Journal of Biological Chemistry. 265 (21): 12111–4. doi: 10.1016/S0021-9258(19)38314-0 . PMID   2197269.
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