Molecular Chaperone HSP70 and Key Regulators of Apoptosis - A Review

Author(s): Rabih Roufayel, Seifedine Kadry*.

Journal Name: Current Molecular Medicine

Volume 19 , Issue 5 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Identified as a molecular chaperone constitutively being synthesized due to enhanced elevated temperature change, this heat shock protein HSP70 has shown to be intimately involved in many protein biogenesis, facilitating the synthesis and folding of proteins and trafficking of nascent peptides during cell growth. HSP70 also plays a vital role in protein assembly, regulation and interaction with a wide variety of proteins. Stress-induced cell death is under the control of the Bcl-2 family of apoptotic regulators and display either pro-apoptotic or anti-apoptotic activities. Subjected to stress conditions such as heat shock, cells have been reported to express elevated expressions of HSP70. Moreover, this molecular chaperon has shown to act at multiple levels to suppress stressed-induced apoptotic signals of some Bcl-2 members by repairing, re-synthesizing damaged proteins, and stabilizing unfolded proteins. Therefore, HSP70 synthesis can act as an essential recovery mode for cellular survival and adaptation during lethal conditions.

Keywords: Molecular chaperone, heat shock proteins, HSP70, apoptosis, Bcl-2 family proteins, caspase.

Kanduc D, Mittelman A, Serpico R, et al. Cell death: Apoptosis versus necrosis.(Review) Int J Oncol 2002; 21(1): 165-70.
Jaattela M, Wissing D, Kokholm K, Kallunki T, Egeblad M. Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 1998; 17: 6124-34.
Kuwana T, Olson NH, Kiosses WB, et al. Pro-apoptotic Bax molecules densely populate the edges of membrane pores. Sci Rep 2016; 6: 27299.
Krumschnabel G, Sohm B, Bock F, Manzl C, Villunger A. The enigma of caspase-2: The laymen’s view. Cell Death Differ 2009; 16: 195-207.
Suzuki HI, Yamagata K, Sugimoto K, et al. Modulation of microRNA processing by p53. Nature 2009; 460(7254): 529-33.
Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 2001; 26: 61-6.
Salvador-Gallego R, Mund M, Cosentino K, et al. Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores. EMBO J 2016; 35(4): 389-401.
Gerner EW, Schneider MJ. Induced thermal resistance in HeLa cells. Nature 1975; 256: 500-2.
Shelton SN, Dillard CD, Robertson J. D. Activation of caspase-9, but not caspase-2 or caspase-8, is essential for heat-induced apoptosis in Jurkat cells. J Biol Chem 2010; 285: 40525-33.
Isomoto H, Oka M, Yano Y, et al. Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer. Cancer Lett 2003; 198: 219-28.
Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104: 487-501.
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL- 2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15(1): 49-63.
Meier P, Finch A, Evan G. Apoptosis in development. Nature 2000; 407: 796-801.
Antonsson B. Bax and other pro-apoptotic Bcl-2 family “killer-proteins” and their victim the mitochondrion. Cell Tissue Res 2001; 306: 347-61.
Hikisz P, Kiliańska ZM. PUMA, a critical mediator of cell death–one decade on from its discovery. Mol Cell Biol 2012; 17: 646-69.
Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis. Nature 2001; 411: 342.
Mosser DD, Morimoto RI. Molecular chaperones and the stress of oncogenesis. Oncogene 2004; 23: 2907-18.
Er E, Oliver L, Cartron PF, et al. Mitochondria as the target of the pro-apoptotic protein Bax. Biochim et Biophy Acta 2006; 1757: 1301-11.
Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 2013; 82: 323-55.
Rohde M, Daugaard M, Jensen MH, et al. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 2005; 19: 570-82.
Tu S, McStay GP, Boucher LM, Mak T, Beere HM, Green DR. In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat Cell Biol 2006; 8: 72-7.
Lithgow T, Strasser A, Driel V, Bertram JF. The Protein Product of the Oncogene bcl-2 is a Component of the Nuclear Envelope, the Endoplasmic Reticulum, and the Outer Mitochondrial Membrane. Cell Growth Differ 1994; 5: 411-7.
Riedl SJ, Salvesen GS. The apoptosome: signaling platform of cell death. Mol Cell Biol 2007; 8: 405-13.
Borner C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 2003; 39: 615-47.
Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228(4706): 1440-3.
Deshaies RJ, Koch BD, Werner-Washburne M, Craig EA, Schekman R. A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature 1988; 332: 800-5.
Yost HJ, Lindquist S. RNA splicing is interrupted by heat shock and is rescued by heat shock protein synthesis. Cell 1986; 45: 185-93.
Milleron RS, Bratton SB. ‘Heated’ debates in apoptosis. Cell Mol Life Sci 2007; 64: 2329-33.
Gotoh T, Terada K, Oyadomari S, Mori M. Hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Cell Death Differ 2004; 11: 390-402.
Iyer V, Chettiar ST, Grover M, Rajyaguru P, Nageshan RK, Tatu U. Giardia lamblia Hsp90 pre-mRNAs undergo self-splicing to generate mature RNA in an in vitro trans-splicing reaction. FEBS Lett 2019; 593(4): 433-42.
Cotter TG. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer 2009; 9: 501-7.
Stankiewicz AR, Lachapelle G, Foo CP, Radicioni SM, Mosser D. D. Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 2005; 280: 38729-39.
Zhang Z, Song T, Zhang T, et al. A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1. Int J Cancer 2011; 128(7): 1724-35.
Tait SWG, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 2010; 11: 621-32.
Buchberger A, Bukau B, Sommer T. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell Biol 2010; 40(2): 238-52.
Beere HM, Wolf BB, Cain K, et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2000; 2: 469-75.
Mosser DD, Caron AW, Bourget L, et al. The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 2000; 20: 7146-59.
Chen HC, Kanai M, Inoue-Yamauchi A, et al. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 2015; 17(10): 1270-81.
Voellmy R, Boellmann F. Chaperone regulation of the heat shock protein response. Adv Exp Med Biol 2007; 594: 89-99.
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Cancer 1972; 26: 239.
Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature 2011; 475: 324-32.
Gavathiotis E, Suzuki M, Davis ML, et al. BAX activation is initiated at a novel interaction site. Nature 2008; 455(7216): 1076-81.
Richter K, Haslbeck M, Buchner J. The heat shock response: life on the vergeof death. Mol Cell Biol 2010; 40(2): 253-66.
Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell Biol 2000; 102: 33-42.
Chipuk JE, Moldoveanu T, Llambi F, et al. The BCL-2 family reunion. Mol Cell Biol 2010; 37: 299-310.
Lazarev VF, Sverchinsky DV, Mikhaylova ER, et al. Sensitizing tumor cells to conventional drugs: HSP70 chaperone inhibitors, their selection and application in cancer models. Cell Death Dis 2018; 9(2): 41.
Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26: 1324-37.
Antignani A, Youle RJ. How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Cell Biol 2006; 18: 685-9.
Meier P, Vousden KH. Lucifer’s labyrinth: ten years of path finding in cell death. Mol Cell Biol 2007; 28: 746-54.
Steel R, Doherty JP, Buzzard K, Clemons N, Hawkins CJ, Anderson RL. Hsp72 inhibits apoptosis upstream of the mitochondria and not through interactions with Apaf-1. J Biol Chem 2004; 279: 51490-9.
Pagliari LJ, Kuwana T, Bonzon C, et al. The multidomain proapoptotic molecules Bax and Bak are directly activated by heat. Proc Natl Acad Sci USA 2005; 102: 17975-80.
Pelham HR. Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 1986; 46: 959-61.
Ritossa F. Discovery of the heat shock response. Cell Stress Chaperones 1996; 1: 97-8.
Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. EMBO J 2011; 30: 3667-83.
Li GC, Mivechi NF, Weitzel G. Heat shock proteins, thermotolerance, and their relevance to clinical hyperthermia. Int J Hyperthermia 1995; 11: 459-88.
Ritossa FM. Experimental activation of specific loci in polytene chromosomes of drosophila. Exp Cell Res 1964; 35: 601-7.
Muchmore SW, Sattler M, Liang H, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996; 38: 335-41.
Cain K, Bratton SB, Cohen GM. The Apaf-1 apoptosome: a large caspase-activating complex. Biochim Biophys Acta 2002; 84: 203-14.
Wilmink GJ, Roth CL, Ibey BL, et al. Identification of microRNAs associated with hyperthermia-induced cellular stress response. Cell Stress Chaperones 2010; 15: 1027-38.
Mirault ME, Goldschmidt-Clermont M, Moran L, Arrigo AP, Tissieres A. The effect of heat shock on gene expression in Drosophila melanogaster. Cold Spring Harb Symp Quant Biol 1978; 42(Pt 2): 819-27.
Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell 2010; 140: 619-30.
Penke B, Paragi G, Gera J, et al. The role of lipids and membranes in the pathogenesis of Alzheimer’s disease: A comprehensive view. Curr Alzheimer Res 2018; 5(13): 1191-2.
Screaton G, Xu XN. T cell life and death signaling via TNF-receptor family members. Curr Opin Immunol 2000; 12: 316-22.
Hanahan D, Weinberg R. The hallmarks of cancer. Cell 2000; 100: 57-70.
Morimoto RI. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 2008; 22: 1427-38.
Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998; 12: 3788-96.
Stankiewicz AR, Livingstone AM, Mohseni N, Mosser DD. Regulation of heat-induced apoptosis by Mcl-1 degradation and its inhibition by Hsp70. Cell Death Differ 2009; 16: 638-47.
Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Cell Biol 2000; 10: 369-77.
Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Cell Biol 2008; 18: 157-64.
Willis SN, Fletcher JI, Kaufmann T, et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 2007; 315(5813): 856-9.
Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity 2009; 30(2): 180-92.
Tsuruta F, Sunayama J, Mori Y, et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 2004; 23: 1889-99.
Taipale M, Jarosz DF, Lindquist S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 2010; 11: 515-28.
Chatterjee S, Burns TF. Targeting heat shock proteins in cancer: A promising therapeutic approach. Int J Mol Sci 2017; 18(9): 1978.
Chirico WJ, Waters MG, Blobel G. 70K heat shock related proteins stimulate protein translocation into microsomes. Nature 1988; 332: 805-10.
Zou H, Li Y, Liu X, Wang X. An APAF-1 Cytochrome c Multimeric Complex is a Functional Apoptosome that Activates Procaspase-9. J Biochem 1999; 274: 11549-56.
Mosser DD, Martin LH. Induced thermotolerance to apoptosis in a human T lymphocyte cell line. J Cell Physiol 1992; 151: 561-70.
Golstein P. Cell death in us and others. Science 1998; 281: 1283-3.
Huang DC, Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell 2000; 103: 839-42.
van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10(5): 389-99.
Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335: 440-2.
Young JC, Agashe VR, Siegers K, Hartl FU. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 2004; 5: 781-91.
Huang DC, Hahne M, Schroeter M, et al. Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL. Proc Natl Acad Sci USA 1999; 96(26): 14871-6.
Pirkkala L, Nykanen P, Sistonen L. Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. FASEB J 2001; 15: 1118-31.
Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491-501.
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9: 47-59.
Krammer PH. CD95’s deadly mission in the immune cells. Nature 2000; 407: 789795.
Zuiderweg ER, Hightower LE, Gestwicki JE. The remarkable multivalency of the Hsp70 chaperones. Cell Stress Chaperones 2017; 22: 173-89.
Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B. Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 1997; 17: 5317-27.
Gabai VL, Meriin AB, Mosser DD, et al. Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 1997; 272: 18033-7.
Zamzami N, Kroemer G. Review: The mitochondrion in apoptosis: how Pandora’s box opens. Mol Cell Biol 2001; 2: 46-57.
Zhang Z, Jin L, Qian X, et al. Novel Bcl-2 Inhibitors: Discovery and mechanism study of small organic apoptosis-inducing agents. ChemBioChem 2007; 8(1): 113-21.
Große L, Wurm CA, Brüser C, et al. Bax assembles into large ring-like structures remodeling the mitochondrial outer membrane in apoptosis. EMBO J 2016; 35(4): 2-13.
Lomonosova E, Chinnadurai G. BH3-only proteins in apoptosis and beyond: An overview. Oncogene 2008; 27: 1-19.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [315 - 325]
Pages: 11
DOI: 10.2174/1566524019666190326114720
Price: $65

Article Metrics

PDF: 20
PRC: 1