vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-02vavilov-4468Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYБелки теплового шока в фолдинге и реактивации белковHeat shock proteins in protein folding and reactivationhttps://orcid.org/0000-0002-7308-8846МалькееваД.MalkeyevaD.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-8786-499XКиселеваЕ. В.KiselevaE. V.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-8257-4654ФёдороваС. А.FedorovaS. A.

Новосибирск

Novosibirsk

fsveta@bionet.nsc.ruФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Курчатовский геномный центр ИЦиГ СО РАНРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Kurchatov Genomic Center of ICG SB RASRussian Federation202502032025291714Copyright © Малькеева Д., Киселева Е.В., Фёдорова С.А., 20252025Малькеева Д., Киселева Е.В., Фёдорова С.А.Malkeyeva D., Kiseleva E.V., Fedorova S.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4468

   В процессе жизнедеятельности в каждой клетке происходят синтез новых белков и удаление старых, денатурированных белков и нерастворимых белковых агрегатов. В поддержании протеостаза значительную роль играют шапероны, которые участвуют в придании правильной конформации (фолдинге) многих белков и способствуют деградации денатурированных или неправильно свернутых белков посредством про теаз или аутофагии. Несмотря на то что фолдинг белков – довольно точный процесс, с возрастом и под воздействием стресса накапливаются ошибки, приводящие к образованию нерастворимых белковых агрегатов, которые могут вызывать различные патологии. Воздействие стрессовых факторов, таких как повышенная температура и изменение кислотности среды, также может способствовать изменению нативной конформации белков, в результате чего они могут не только терять выполняемые в норме функции, но и приобретать новые цитотоксические свойства. В связи с увеличением средней продолжительности жизни человека в мире отмечается рост протеинопатий – заболеваний, связанных с нарушением протеостаза, к которым относятся, например, болезни Альцгеймера, Паркинсона, Хантингтона; поэтому выявление механизмов, препятствующих накоплению и способствующих удалению цитотоксичных агрегатов, стало актуальной задачей. Белки теплового шока (heat shock proteins, HSP) – молекулярные шапероны, принимающие участие как в придании правильной конформации вновь синтезированным белкам, так и в рефолдинге денатурированных белков с их последующей реактивацией. HSP разнообразны по структуре и выполняемым функциям и встречаются у всех изученных про- и эукариотических организмов. HSP синтезируются в клетке постоянно. Выработка множества из них многократно усиливается при стрессах, включая тепловой (за что они и получили свое название) и метаболический стресс, возникающий из-за повышения количества неправильно свернутых белков. В настоящем обзоре описаны механизмы действия и функции представителей пяти семейств HSP в фолдинге и реактивации белков.

   Throughout their lives, cells synthesise new and dispose of the old, denatured proteins and insoluble protein aggregates. An important role in maintaining proteostasis is played by chaperones, which fold various proteins and promote degradation of denatured or misfolded proteins via proteasomes or autophagy. Despite protein folding being an accurate process, as organisms age and experience stress, errors accumulate, which leads to the formation of protein aggregates that can result in pathological changes. In addition, stress factors such as elevated temperature and altered pH can promote protein denaturation that can result in the proteins not only losing their native functions, but also gaining novel cytotoxic properties. With the increase of human average lifespan, more and more cases of proteinopathies – diseases caused by disruptions in proteostasis, e. g. Alzheimer’s disease, Huntington’s disease etc. – emerge. Therefore, identification of mechanisms preventing the formation of cytotoxic protein aggregates and promoting their clearance is of high importance. Heat shock proteins (HSPs) are the molecular chaperones involved in folding nascent proteins and refolding the denatured ones, leading to their reactivation. Heat shock proteins vary in structure and functions and are found in all prokaryotes and eukaryotes discovered to date. HSPs are constantly synthesised in cells under normal conditions, and a multitude of them are dramatically up-regulated during stress, which includes heat shock (which earned them their name) and metabolic stress caused by the increased numbers of misfolded proteins. In this review, we describe mechanisms of action and functions of members of five heat shock protein families.

белки теплового шокамолекулярные шапероныфолдинг белковконтроль качества белковHSPheat shock proteinsmolecular chaperonesprotein foldingprotein quality controlHSPРабота Киселевой Е.В. и Фёдоровой С.А. поддержана программой фундаментальных научных исследований по проекту № FWNR-2022-0015.E.V. Kiseleva and S.A. Fedorova were supported by the Ministry of Science and Higher Education of the Russian Federation, project No. FWNR-2022-0015ReferencesAvellaneda M.J., Franke K.B., Sunderlikova V., Bukau B., Mogk A., Tans S.J. Processive extrusion of polypeptide loops by a Hsp100 disaggregase. Nature. 2020;578(7794):317-320. doi: 10.1038/s41586-020-1964-yAvellaneda M.J., Franke K.B., Sunderlikova V., Bukau B., Mogk A., Tans S.J. Processive extrusion of polypeptide loops by a Hsp100 disaggregase. Nature. 2020;578(7794):317-320. doi: 10.1038/s41586-020-1964-yBar-Lavan Y., Shemesh N., Ben-Zvi A. Chaperone families and interactions in metazoa. Essays Biochem. 2016;60(2):237-253. doi: 10.1042/EBC20160004Bar-Lavan Y., Shemesh N., Ben-Zvi A. Chaperone families and interactions in metazoa. Essays Biochem. 2016;60(2):237-253. doi: 10.1042/EBC20160004Brocchieri L., Conway de Macario E., Macario A.J. Hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol. 2008;8(1):19. doi 10.1186/1471-2148-8-19Brocchieri L., Conway de Macario E., Macario A.J. Hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol. 2008;8(1):19. doi 10.1186/1471-2148-8-19Clare D.K., Vasishtan D., Stagg S., Quispe J., Farr G.W., Topf M., Horwich A.L., Saibil H.R. ATP-triggered conformational changes de lineate substrate-binding and -folding mechanics of the GroEL cha peronin. Cell. 2012;149(1):113-123. doi: 10.1016/j.cell.2012.02.047Clare D.K., Vasishtan D., Stagg S., Quispe J., Farr G.W., Topf M., Horwich A.L., Saibil H.R. ATP-triggered conformational changes de lineate substrate-binding and -folding mechanics of the GroEL cha peronin. Cell. 2012;149(1):113-123. doi: 10.1016/j.cell.2012.02.047Duran E.C., Weaver C.L., Lucius A.L. Comparative analysis of the structure and function of AAA+ motors ClpA, ClpB, and Hsp104: common threads and disparate functions. Front Mol Biosci. 2017; 4:54. doi: 10.3389/fmolb.2017.00054Duran E.C., Weaver C.L., Lucius A.L. Comparative analysis of the structure and function of AAA+ motors ClpA, ClpB, and Hsp104: common threads and disparate functions. Front Mol Biosci. 2017; 4:54. doi: 10.3389/fmolb.2017.00054Ellis J. Proteins as molecular chaperones. Nature. 1987;328(6129): 378-379. doi: 10.1038/328378a0Ellis J. Proteins as molecular chaperones. Nature. 1987;328(6129): 378-379. doi: 10.1038/328378a0Fan F., Duan Y., Yang F., Trexler C., Wang H., Huang L., Li Y., Tang H., Wang G., Fang X., Liu J., Jia N., Chen J., Ouyang K. Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure. Cell Death Differ. 2020;27(2):587-600. doi: 10.1038/s41418-019-0374-xFan F., Duan Y., Yang F., Trexler C., Wang H., Huang L., Li Y., Tang H., Wang G., Fang X., Liu J., Jia N., Chen J., Ouyang K. Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure. Cell Death Differ. 2020;27(2):587-600. doi: 10.1038/s41418-019-0374-xFeder M.E., Hofmann G.E. Heat-shock proteins, molecular chapero nes, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol. 1999;61(1):243-282. doi: 10.1146/annurev.physiol.61.1.243Feder M.E., Hofmann G.E. Heat-shock proteins, molecular chapero nes, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol. 1999;61(1):243-282. doi: 10.1146/annurev.physiol.61.1.243Fu X. Insights into how small heat shock proteins bind a great diversity of substrate proteins: a super-transformer model. In: Tanguay R.M., Hightower L.E. (Eds) The Big Book on Small Heat Shock Proteins. Cham: Springer Int. Pub., 2015;107-117. doi: 10.1007/978-3-319-16077-1_4Fu X. Insights into how small heat shock proteins bind a great diversity of substrate proteins: a super-transformer model. In: Tanguay R.M., Hightower L.E. (Eds) The Big Book on Small Heat Shock Proteins. Cham: Springer Int. Pub., 2015;107-117. doi: 10.1007/978-3-319-16077-1_4Hayer-Hartl M. From chaperonins to Rubisco assembly and metabolic repair. Protein Sci. 2017;26(12):2324-2333. doi: 10.1002/pro.3309Hayer-Hartl M. From chaperonins to Rubisco assembly and metabolic repair. Protein Sci. 2017;26(12):2324-2333. doi: 10.1002/pro.3309Hemmingsen S.M. What is a chaperonin? Nature. 1992;357(6380): 650-650. doi: 10.1038/357650b0Hemmingsen S.M. What is a chaperonin? Nature. 1992;357(6380): 650-650. doi: 10.1038/357650b0Hodson S., Marshall J.J.T., Burston S.G. Mapping the road to recovery: the ClpB/Hsp104 molecular chaperone. J Struct Biol. 2012;179(2): 161-171. doi: 10.1016/j.jsb.2012.05.015Hodson S., Marshall J.J.T., Burston S.G. Mapping the road to recovery: the ClpB/Hsp104 molecular chaperone. J Struct Biol. 2012;179(2): 161-171. doi: 10.1016/j.jsb.2012.05.015Horwich A.L. Protein folding in the cell: an inside story. Nat Med. 2011;17(10):1211-1216. doi: 10.1038/nm.2468Horwich A.L. Protein folding in the cell: an inside story. Nat Med. 2011;17(10):1211-1216. doi: 10.1038/nm.2468Jolly C., Morimoto R.I. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst. 2000;92(19):1564-1572. doi: 10.1093/jnci/92.19.1564Jolly C., Morimoto R.I. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst. 2000;92(19):1564-1572. doi: 10.1093/jnci/92.19.1564Kakkar V., Meister-Broekema M., Minoia M., Carra S., Kampinga H.H. Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech. 2014;7(4):421-434. doi: 10.1242/dmm.014563Kakkar V., Meister-Broekema M., Minoia M., Carra S., Kampinga H.H. Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech. 2014;7(4):421-434. doi: 10.1242/dmm.014563Kampinga H.H., Hageman J., Vos M.J., Kubota H., Tanguay R.M., Bruford E.A., Cheetham M.E., Chen B., Hightower L.E. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones. 2009;14(1):105-111. doi: 10.1007/s12192-008-0068-7Kampinga H.H., Hageman J., Vos M.J., Kubota H., Tanguay R.M., Bruford E.A., Cheetham M.E., Chen B., Hightower L.E. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones. 2009;14(1):105-111. doi: 10.1007/s12192-008-0068-7Koumoto Y., Shimada T., Kondo M., Hara-Nishimura I., Nishimura M. Chloroplasts have a novel Cpn10 in addition to Cpn20 as co-chaperonins in Arabidopsis thaliana. J Biol Chem. 2001;276(32): 29688-29694. doi: 10.1074/jbc.M102330200Koumoto Y., Shimada T., Kondo M., Hara-Nishimura I., Nishimura M. Chloroplasts have a novel Cpn10 in addition to Cpn20 as co-chaperonins in Arabidopsis thaliana. J Biol Chem. 2001;276(32): 29688-29694. doi: 10.1074/jbc.M102330200Kumar C.M.S., Mande S.C., Mahajan G. Multiple chaperonins in bacteria-novel functions and non-canonical behaviors. Cell Stress Chaperones. 2015;20(4):555-574. doi: 10.1007/s12192-015-0598-8Kumar C.M.S., Mande S.C., Mahajan G. Multiple chaperonins in bacteria-novel functions and non-canonical behaviors. Cell Stress Chaperones. 2015;20(4):555-574. doi: 10.1007/s12192-015-0598-8Larburu N., Adams C.J., Chen C.-S., Nowak P.R., Ali M.M.U. Mechanism of Hsp70 specialized interactions in protein translocation and the unfolded protein response. Open Biol. 2020;10(8):200089. doi: 10.1098/rsob.200089Larburu N., Adams C.J., Chen C.-S., Nowak P.R., Ali M.M.U. Mechanism of Hsp70 specialized interactions in protein translocation and the unfolded protein response. Open Biol. 2020;10(8):200089. doi: 10.1098/rsob.200089Li J., Buchner J. Structure, function and regulation of the Hsp90 machinery. Biomed J. 2013;36(3):106-117. doi: 10.4103/2319-4170.113230Li J., Buchner J. Structure, function and regulation of the Hsp90 machinery. Biomed J. 2013;36(3):106-117. doi: 10.4103/2319-4170.113230Lindquist S. The heat-shock response. Annu Rev Biochem. 1986;55(1): 1151-1191. doi: 10.1146/annurev.bi.55.070186.005443Lindquist S. The heat-shock response. Annu Rev Biochem. 1986;55(1): 1151-1191. doi: 10.1146/annurev.bi.55.070186.005443Lopez T., Dalton K., Frydman J. The mechanism and function of group II chaperonins. J Mol Biol. 2015;427(18):2919-2930. doi: 10.1016/j.jmb.2015.04.013Lopez T., Dalton K., Frydman J. The mechanism and function of group II chaperonins. J Mol Biol. 2015;427(18):2919-2930. doi: 10.1016/j.jmb.2015.04.013Macario A.J.L., Grippo T.M., de Macario E.C. Genetic disorders involving molecular-chaperone genes: a perspective. Genet Med. 2005;7(1):3-12. doi: 10.1097/01.GIM.0000151351.11876.C3Macario A.J.L., Grippo T.M., de Macario E.C. Genetic disorders involving molecular-chaperone genes: a perspective. Genet Med. 2005;7(1):3-12. doi: 10.1097/01.GIM.0000151351.11876.C3Mogk A., Kummer E., Bukau B. Cooperation of Hsp70 and Hsp100 chaperone machines in protein disaggregation. Front Mol Biosci. 2015;2:22. doi: 10.3389/fmolb.2015.00022Mogk A., Kummer E., Bukau B. Cooperation of Hsp70 and Hsp100 chaperone machines in protein disaggregation. Front Mol Biosci. 2015;2:22. doi: 10.3389/fmolb.2015.00022Mogk A., Ruger-Herreros C., Bukau B. Cellular functions and mechanisms of action of small heat shock proteins. Annu Rev Microbiol. 2019;73(1):89-110. doi: 10.1146/annurev-micro-020518-115515Mogk A., Ruger-Herreros C., Bukau B. Cellular functions and mechanisms of action of small heat shock proteins. Annu Rev Microbiol. 2019;73(1):89-110. doi: 10.1146/annurev-micro-020518-115515Mokry D.Z., Abrahão J., Ramos C.H.I. Disaggregases, molecular chaperones that resolubilize protein aggregates. An Acad Bras Cienc. 2015;87(2 suppl):1273-1292. doi: 10.1590/0001-3765201520140671Mokry D.Z., Abrahão J., Ramos C.H.I. Disaggregases, molecular chaperones that resolubilize protein aggregates. An Acad Bras Cienc. 2015;87(2 suppl):1273-1292. doi: 10.1590/0001-3765201520140671Paul A., Rao S., Mathur S. The α-crystallin domain containing genes: identification, phylogeny and expression profiling in abiotic stress, phytohormone response and development in tomato (Solanum lyco persicum). Front Plant Sci. 2016;7:426. doi: 10.3389/fpls.2016.00426Paul A., Rao S., Mathur S. The α-crystallin domain containing genes: identification, phylogeny and expression profiling in abiotic stress, phytohormone response and development in tomato (Solanum lyco persicum). Front Plant Sci. 2016;7:426. doi: 10.3389/fpls.2016.00426Radons J. The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones. 2016;21(3):379-404. doi: 10.1007/s12192-016-0676-6Radons J. The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones. 2016;21(3):379-404. doi: 10.1007/s12192-016-0676-6Rosenzweig R., Nillegoda N.B., Mayer M.P., Bukau B. The Hsp70 chaperone network. Nat Rev Mol Cell Biol. 2019;20(11):665-680. doi: 10.1038/s41580-019-0133-3Rosenzweig R., Nillegoda N.B., Mayer M.P., Bukau B. The Hsp70 chaperone network. Nat Rev Mol Cell Biol. 2019;20(11):665-680. doi: 10.1038/s41580-019-0133-3Saibil H. Chaperone machines for protein folding, unfolding and disaggregation. Nat Rev Mol Cell Biol. 2013;14(10):630-642. doi: 10.1038/nrm3658Saibil H. Chaperone machines for protein folding, unfolding and disaggregation. Nat Rev Mol Cell Biol. 2013;14(10):630-642. doi: 10.1038/nrm3658Saji H., Iizuka R., Yoshida T., Abe T., Kidokoro S., Ishii N., Yohda M. Role of the IXI/V motif in oligomer assembly and function of StHsp14.0, a small heat shock protein from the acidothermophilic archaeon, Sulfolobus tokodaii strain 7. Proteins Struct Funct Bioin form. 2008;71(2):771-782. doi: 10.1002/prot.21762Saji H., Iizuka R., Yoshida T., Abe T., Kidokoro S., Ishii N., Yohda M. Role of the IXI/V motif in oligomer assembly and function of StHsp14.0, a small heat shock protein from the acidothermophilic archaeon, Sulfolobus tokodaii strain 7. Proteins Struct Funct Bioin form. 2008;71(2):771-782. doi: 10.1002/prot.21762Sarkar S., Singh M.D., Yadav R., Arunkumar K.P., Pittman G.W. Heat shock proteins: molecules with assorted functions. Front Biol (Beijing). 2011;6(4):312. doi: 10.1007/s11515-011-1080-3Sarkar S., Singh M.D., Yadav R., Arunkumar K.P., Pittman G.W. Heat shock proteins: molecules with assorted functions. Front Biol (Beijing). 2011;6(4):312. doi: 10.1007/s11515-011-1080-3Sørensen J.G., Kristensen T.N., Loeschcke V. The evolutionary and ecological role of heat shock proteins. Ecol Lett. 2003;6(11):1025-1037. doi: 10.1046/j.1461-0248.2003.00528Sørensen J.G., Kristensen T.N., Loeschcke V. The evolutionary and ecological role of heat shock proteins. Ecol Lett. 2003;6(11):1025-1037. doi: 10.1046/j.1461-0248.2003.00528Tower J. Heat shock proteins and Drosophila aging. Exp Gerontol. 2011;46(5):355-362. doi: 10.1016/j.exger.2010.09.002Tower J. Heat shock proteins and Drosophila aging. Exp Gerontol. 2011;46(5):355-362. doi: 10.1016/j.exger.2010.09.002van Leeuwen F.W., Kampinga H.H. Heat shock proteins and protein quality control in Alzheimer’s disease. In: Wolfe M.S. (Ed.) The Molecular and Cellular Basis of Neurodegenerative Diseases. Academic Press, 2018;269-298. doi: 10.1016/B978-0-12-811304-2.00010-9van Leeuwen F.W., Kampinga H.H. Heat shock proteins and protein quality control in Alzheimer’s disease. In: Wolfe M.S. (Ed.) The Molecular and Cellular Basis of Neurodegenerative Diseases. Academic Press, 2018;269-298. doi: 10.1016/B978-0-12-811304-2.00010-9Xiao C., Hull D., Qiu S., Yeung J., Zheng J., Barwell T., Robertson R.M., Seroude L. Expression of heat shock protein 70 is insufficient to extend Drosophila melanogaster longevity. G3 (Bethesda). 2019;9(12):4197-4207. doi: 10.1534/g3.119.400782Xiao C., Hull D., Qiu S., Yeung J., Zheng J., Barwell T., Robertson R.M., Seroude L. Expression of heat shock protein 70 is insufficient to extend Drosophila melanogaster longevity. G3 (Bethesda). 2019;9(12):4197-4207. doi: 10.1534/g3.119.400782Zhang S., Zhou H., Yu F., Bai C., Zhao Q., He J., Liu C. Structural insight into the cooperation of chloroplast chaperonin subunits. BMC Biol. 2016;14(1):29. doi: 10.1186/s12915-016-0251-8Zhang S., Zhou H., Yu F., Bai C., Zhao Q., He J., Liu C. Structural insight into the cooperation of chloroplast chaperonin subunits. BMC Biol. 2016;14(1):29. doi: 10.1186/s12915-016-0251-8Żwirowski S., Kłosowska A., Obuchowski I., Nillegoda N.B., Piróg A., Ziętkiewicz S., Bukau B., Mogk A., Liberek K. Hsp70 displaces small heat shock proteins from aggregates to initiate protein refolding. EMBO J. 2017;36(6):783-796. doi: 10.15252/embj.201593378Żwirowski S., Kłosowska A., Obuchowski I., Nillegoda N.B., Piróg A., Ziętkiewicz S., Bukau B., Mogk A., Liberek K. Hsp70 displaces small heat shock proteins from aggregates to initiate protein refolding. EMBO J. 2017;36(6):783-796. doi: 10.15252/embj.201593378

The authors declare that there are no conflicts of interest present.