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Interaction between the inducible 70-kDa heat shock protein and autophagy: effects on fertility and pregnancy

  • Perspective and Reflection Article
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Cell Stress and Chaperones Aims and scope

Abstract

A consequence of hsp70 (HSPA1A) induction is the inhibition of autophagy. Evidence of autophagy involvement in all aspects of the reproductive process is reviewed, and possible consequences of hsp70 induction at each developmental stage are postulated. It is proposed that aberrant external or internal stimuli that result in high levels of hsp70 production interfere with normal autophagy-related functions and lead to a decrease in the number of functional ova and spermatozoa, impaired pre- and post-implantation embryo development, and increased susceptibility to premature labor and delivery. The purpose of this review is to increase understanding of hsp70-autophagy interactions during reproduction. Interventions to modulate this interaction will lead to development of novel protocols to improve fertility and pregnancy outcome.

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References

  • Adhikari D, Zheng W, Shen Y, Gorre N, Hämäläinen T, Cooney AJ, Huhtaniemi I, Lan Z, Liu K (2010) Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet 19(3):397–410

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, Witkin SS (2008) Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod immunol 79:12–17

    Article  CAS  PubMed  Google Scholar 

  • Beere HM, Wolf BB, Cain K et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nature Cell Biol 2:469–475

    Article  CAS  PubMed  Google Scholar 

  • Brenu EW, Staines DR, Tajouri L, Huth T, Ashton KJ (2013) Marshall-Gradisnik SM (2013) Heat shock proteins and regulatory T cells. Autoimmune Dis 2013:813256

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bustamante-Marin X, Quiroga C, Lavandero S, Reyes JG, Moreno RD (2012) Apoptosis, necrosis and autophagy are influenced by metabolic energy sources in cultured rat spermatocytes. Apoptosis 17:539–550

    Article  CAS  PubMed  Google Scholar 

  • Chaiworapongsa T, Erez O, Kusanovic JP et al (2008) Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition. J Matern Fetal Neonatal Med 21:449–461

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chang YL, Wang TH, Chang SD, Chao AS, Hsieh PC, Wang CN (2013) Increased autophagy in the placental territory of selective intrauterine growth-restricted monochorionic twins. Prenat Diagn 33(2):187–190

    Article  PubMed  Google Scholar 

  • Chen GQ, Zhang H, Qi HB, Yao ZW, Gao L, Qiu CL (2012) Effects and mechanisms of autophagy of trophoblast cells in severe preeclampsia. Xi bao yu fen zi mian yi xue za zhi (Chin J Cell Mol Immunol 28:294–296

    CAS  Google Scholar 

  • Chou SD, Prince T, Gong J, Calderwood SK (2012) mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS One 7, e39679

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Choy A, Roy CR (2013) Autophagy and bacterial infection: an evolving arms race. Trends Microbiol 21(9):451–456

    Article  CAS  PubMed  Google Scholar 

  • Curtis S, Jones CJ, Garrod A, Hulme CH, Heazell AE (2013) Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction. J Matern Fetal Neonatal Med 26:339–346

    Article  CAS  PubMed  Google Scholar 

  • Dokladny K, Zuhl MN, Mandell M et al (2013) Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy. J BIol Chem 288:14959–14972

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dokladny K, Myers OB, Moseley PL (2015) Heat shock response and autophagy–cooperation and control. Autophagy 11(2):200–213

    Article  PubMed  Google Scholar 

  • Doulaveris G, Orfanelli T, Benn K, Zervoudakis I, Skupski D, Witkin SS (2013) A polymorphism in an autophagy-related gene, ATG16L1, influences time to delivery in women with an unfavorable cervix who require labor induction. J Perinatal Med 41:411–414

    Article  CAS  Google Scholar 

  • Gabai VL, Meriin AB, Mosser DD et al (1997) Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 272:18033–18037

    Article  CAS  PubMed  Google Scholar 

  • Gallardo Bolanos JM, Miro Moran A, Balao da Silva CM et al (2012) Autophagy and apoptosis have a role in the survival or death of stallion spermatozoa during conservation in refrigeration. PLoS One 7, e30688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gao L, Qi HB, Kamana KC, Zhang XM, Zhang H, Baker PN (2015) Excessive autophagy induces the failure of trophoblast invasion and vasculature: possible relevance to the pathogenesis of preeclampsia. J Hypertens 33(1):106–117

    Article  CAS  PubMed  Google Scholar 

  • Giraldo P, Neuer A, Ribeiro-Filho A, Linhares I, Witkin SS (1999) Detection of the human 70-kD and 60-kD heat shock proteins in the vagina: relation to microbial flora, vaginal pH, and method of contraception. Infect Dis Obstet Gynecol 7:23–25

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23(16):2891–2906

    Article  CAS  PubMed  Google Scholar 

  • Gustafsson AB, Gottlieb RA (2008) Recycle or die: the role of autophagy in cardioprotection. J Mol Cell Cardiol 44(4):654–661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hirota Y, Cha J, Yoshie M, Daikoku T, Dey SK (2011) Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice. Proc Natl Acad Sci U S A 108:18073–18078

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hromadnikova I, Dvorakova L, Kotlabova K et al (2015) Assessment of placental and maternal stress responses in patients with pregnancy related complications via monitoring of heat shock protein mRNA levels. Molec Biol Reports 42:625–637

    Article  CAS  Google Scholar 

  • Hung TH, Chen SF, Lo LM, Li MJ, Yeh YL, Hsieh TT (2012) Increased autophagy in placentas of intrauterine growth-restricted pregnancies. PLoS One 7, e40957

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jean-Pierre C, Perni SC, Bongiovanni AM et al (2006) Extracellular 70-kd heat shock protein in mid-trimester amniotic fluid and its effect on cytokine production by ex vivo-cultured amniotic fluid cells. Am J Obstet Gynecol 194:694–698

    Article  CAS  PubMed  Google Scholar 

  • Johnstone ED, Sawicki G, Guilbert L, Winkler-Lowen B, Cadete VJ, Morrish DW (2011) Differential proteomic analysis of highly purified placental cytotrophoblasts in pre-eclampsia demonstrates a state of increased oxidative stress and reduced cytotrophoblast antioxidant defense. Proteomics 11:4077–4084

    Article  CAS  PubMed  Google Scholar 

  • Kanninen TT, de Andrade Ramos BR, Witkin SS (2013) The role of autophagy in reproduction from gametogenesis to parturition. Eur J Obstet Gynecol Reprod Biol 171:3–8

    Article  CAS  PubMed  Google Scholar 

  • Kanninen TT, Jayaram A, Jaffe Lifshitz S, Witkin SS (2014a) Altered autophagy induction by sera from pregnant women with pre-eclampsia: a case-control study. BJOG 121:958–964

    Article  CAS  PubMed  Google Scholar 

  • Kanninen TT, Sisti G, Witkin SS (2014b) Induction of the 70 kDa heat shock protein stress response inhibits autophagy: possible consequences for pregnancy outcome. J Matern Fetal Neonatal Med 1–4:1476–7058. doi:10.3109/14767058.2014.991916

    Google Scholar 

  • Lee JE, Oh HA, Song H, Jun JH, Roh CR, Xie H, Dey SK, Lim HJ (2011) Autophagy regulates embryonic survival during delayed implantation. Endocrinology 152:2067–2075

    Article  CAS  PubMed  Google Scholar 

  • Levine B (2005) Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120:159–162

    CAS  PubMed  Google Scholar 

  • Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469:323–335

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li F, Vierstra RD (2012) Autophagy: a multifaceted intracellular system for bulk and selective recycling. Trends Plant Sci 17:526–537

    Article  CAS  PubMed  Google Scholar 

  • Lutsenko MT, Dorofienko NN, Andrievskaya IA (2010) Morphofunctional characteristics of syncytiotrophoblast and content of heat shock protein 70 in it during exacerbation of herpesvirus infection in pregnant women. Bull Exp Biol Med 150:149–152

    Article  CAS  PubMed  Google Scholar 

  • Mailath-Pokorny M, Polterauer S, Kohl M et al (2015) Individualized assessment of preterm birth risk using two modified prediction models. Eur J Obstet Gynecol Reprod Biol 186:42–48

    Article  PubMed  Google Scholar 

  • Maiuri MC, Zalchvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Molec Cell Biol 8:741–752

    Article  CAS  Google Scholar 

  • Menon R, Gerber S, Fortunato SJ, Witkin SS (2001) Lipopolysaccharide stimulation of 70 kilo Dalton heat shock protein messenger ribonucleic acid production in cultured human fetal membranes. J Perinatal Med 29:133–136

    Article  CAS  Google Scholar 

  • Molvarec A, Rigo J Jr, Lazar L et al (2009) Increased serum heat-shock protein 70 levels reflect systemic inflammation, oxidative stress and hepatocellular injury in preeclampsia. Cell Stress Chaperones 14:151–159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakashima A, Yamanaka-Tatematsu M, Fujita N et al (2013) Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia. Autophagy 9:303–316

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Oh SY, Choi SJ, Kim KH, Cho EY, Kim JH, Roh CR (2008) Autophagy-related proteins, LC3 and Beclin-1, in placentas from pregnancies complicated by preeclampsia. Reprod Sci 15:912–920

    Article  CAS  PubMed  Google Scholar 

  • Parsell DA, Lindquist S (1993) The function of heat –shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genetics 27:437–496

    Article  CAS  Google Scholar 

  • Ralph SG, Rutherford AJ, Wilson JD (1999) Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 319:220–223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ramos BA, Kanninen TT, Sisti G, Witkin SS (2015) Microorganisms in the female genital tract during pregnancy: tolerance versus pathogenesis. Am J Reprod Immunol 73:383–389

    Article  Google Scholar 

  • Reddy P, Liu L, Adhikari D et al (2008) Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 319:611–613

    Article  CAS  PubMed  Google Scholar 

  • Redman CW, Tannetta DS, Dragovic RA et al (2012) Review: Does size matter? Placental debris and the pathophysiology of pre-eclampsia. Placenta 33(Suppl):S48–S54

    Article  PubMed  Google Scholar 

  • Romero R, Gomez R, Chaiworapongsa T, Conoscenti G, Kim JC, Kim YM (2001) The role of infection in preterm labour and delivery. Paediatric Perinatal Epidemiol 15(Suppl 2):41–56

    Article  Google Scholar 

  • Saito S, Nakashima A (2013) Review: The role of autophagy in extravillous trophoblast function under hypoxia. Placenta 34(Suppl):S79–S84

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Sato K (2011) Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos. Science 334:1141–1144

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Sato K (2012) Maternal inheritance of mitochondrial DNA: degradation of paternal mitochondria by allogeneic organelle autophagy, allophagy. Autophagy 8:424–425

    Article  CAS  PubMed  Google Scholar 

  • Scieglinska D, Krawczyk Z (2015) Expression, function, and regulation of the testis-enriched heat shock HSPA2 gene in rodents and humans. Cell Stress Chaperones 20(2):221–235

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Signorelli P, Avagliano L, Virgili E et al (2011) Autophagy in term normal human placentas. Placenta 32:482–485

    Article  CAS  PubMed  Google Scholar 

  • Sirotkin AV, Bauer M (2011) Heat shock proteins in porcine ovary: synthesis, accumulation and regulation by stress and hormones. Cell Stress Chaperones 16:379–387

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Song BS, Yoon SB, Kim JS et al (2012) Induction of autophagy promotes preattachment development of bovine embryos by reducing endoplasmic reticulum stress. Biol Reprod 87(8):1–11

    Google Scholar 

  • Spandorfer SD, Neuer A, Giraldo PC, Rosenwaks Z, Witkin SS (2001) Relationship of abnormal vaginal flora, proinflammatory cytokines and idiopathic infertility in women undergoing IVF. J Reprod Med 46:806–810

    CAS  PubMed  Google Scholar 

  • Tan H, Xu Y, Xu J et al (2007) Association of increased heat shock protein 70 levels in the lymphocyte with high risk of adverse pregnancy outcomes in early pregnancy: a nested case-control study. Cell Stress Chaperones 12:230–236

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thorburn A (2014) Autophagy and its effects: making sense of double-edged swords. PLoS Biol 12(10), e1001967

    Article  PubMed Central  PubMed  Google Scholar 

  • Tsukamoto S, Kuma A, Murakami M, Kishi C, Yamamoto A, Mizushima N (2008) Autophagy is essential for preimplantation development of mouse embryos. Science 321:117–120

    Article  CAS  PubMed  Google Scholar 

  • Wilson JD, Ralph SG, Rutherford AJ (2002) Rates of bacterial vaginosis in women undergoing in vitro fertilisation for different types of infertility. BJOG 109:714–717

    Article  PubMed  Google Scholar 

  • Witkin SS, Linhares IM (2010) Heat shock proteins, genital tract infections and reproductive outcome. In: Pockley AG, Calderwood SK, Santoro MG (eds) Prokaryotic and eukaryotic heat shock proteins in infectious disease. Springer, Netherlands, pp 241–256

    Google Scholar 

  • Wittig S, Hensse S, Keitel C, Elsner C, Wittig B (1983) Heat shock gene expression is regulated during teratocarcinoma cell differentiation and early embryonic development. Devel Biol 96:507–514

    Article  CAS  Google Scholar 

  • Yu L, Alva A, Su H et al (2004a) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304:1500–1502

    Article  CAS  PubMed  Google Scholar 

  • Yu L, Lenardo MJ, Baehrecke EH (2004b) Autophagy and caspases: a new cell death program. Cell Cycle 3:1124–1126

    CAS  PubMed  Google Scholar 

  • Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ (2014) Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia. J Pathol 234:262–276

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA

    Giovanni Sisti, Tomi T. Kanninen, Ilana Ramer & Steven S. Witkin

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  1. Giovanni Sisti
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  2. Tomi T. Kanninen
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  3. Ilana Ramer
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  4. Steven S. Witkin
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Correspondence to Steven S. Witkin.

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Sisti, G., Kanninen, T.T., Ramer, I. et al. Interaction between the inducible 70-kDa heat shock protein and autophagy: effects on fertility and pregnancy. Cell Stress and Chaperones 20, 753–758 (2015). https://doi.org/10.1007/s12192-015-0609-9

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  • DOI: https://doi.org/10.1007/s12192-015-0609-9

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