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Heat Shock Protein A2 (HSPA2): Regulatory Roles in Germ Cell Development and Sperm Function

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The Role of Heat Shock Proteins in Reproductive System Development and Function

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 222))

Abstract

Among the numerous families of heat shock protein (HSP) that have been implicated in the regulation of reproductive system development and function, those belonging to the 70 kDa HSP family have emerged as being indispensable for male fertility. In particular, the testis-enriched heat shock 70 kDa protein 2 (HSPA2) has been shown to be critical for the progression of germ cell differentiation during spermatogenesis in the mouse model. Beyond this developmentally important window, mounting evidence has also implicated HSPA2 in the functional transformation of the human sperm cell during their ascent of the female reproductive tract. Specifically, HSPA2 appears to coordinate the remodelling of specialised sperm domains overlying the anterior region of the sperm head compatible with their principle role in oocyte recognition. The fact that levels of the HSPA2 protein in mature spermatozoa tightly correlate with the efficacy of oocyte binding highlight its utility as a powerful prognostic biomarker of male fertility. In this chapter, we consider the unique structural and biochemical characteristics of HSPA2 that enable this heat shock protein to fulfil its prominent roles in orchestrating the morphological differentiation of male germ cells during spermatogenesis as well as their functional transformation during post-testicular sperm maturation.

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References

  • Adly MA, Assaf HA, Hussein MR (2008) Heat shock protein 27 expression in the human testis showing normal and abnormal spermatogenesis. Cell Biol Int 32(10):1247–1255. doi:10.1016/j.cellbi.2008.07.009

    Article  CAS  PubMed  Google Scholar 

  • Agarwal A, Sharma R, Samanta L, Durairajanayagam D, Sabanegh E (2016) Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility. Asian J Androl 18(2):282–291. doi:10.4103/1008-682X.170445

    Article  CAS  PubMed  Google Scholar 

  • Aitken RJ, Whiting S, De Iuliis GN, McClymont S, Mitchell LA, Baker MA (2012) Electrophilic aldehydes generated by sperm metabolism activate mitochondrial reactive oxygen species generation and apoptosis by targeting succinate dehydrogenase. J Biol Chem 287(39):33048–33060. doi:10.1074/jbc.M112.366690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aitken RJ, Smith TB, Jobling MS, Baker MA, De Iuliis GN (2014) Oxidative stress and male reproductive health. Asian J Androl 16(1):31–38. doi:10.4103/1008-682X.122203

    Article  CAS  PubMed  Google Scholar 

  • Alekseev OM, Richardson RT, O’Rand MG (2009) Linker histones stimulate HSPA2 ATPase activity through NASP binding and inhibit CDC2/Cyclin B1 complex formation during meiosis in the mouse. Biol Reprod 81(4):739–748. doi:10.1095/biolreprod.109.076497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen RL, O’Brien DA, Eddy EM (1988a) A novel hsp70-like protein (P70) is present in mouse spermatogenic cells. Mol Cell Biol 8(2):828–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen RL, O’Brien DA, Jones CC, Rockett DL, Eddy EM (1988b) Expression of heat shock proteins by isolated mouse spermatogenic cells. Mol Cell Biol 8(8):3260–3266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen JW, Dix DJ, Collins BW, Merrick BA, He C, Selkirk JK, Poorman-Allen P, Dresser ME, Eddy EM (1996) HSP70-2 is part of the synaptonemal complex in mouse and hamster spermatocytes. Chromosoma 104(6):414–421

    Article  CAS  PubMed  Google Scholar 

  • Aprile FA, Dhulesia A, Stengel F, Roodveldt C, Benesch JL, Tortora P, Robinson CV, Salvatella X, Dobson CM, Cremades N (2013) Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain. PLoS One 8(6):e67961. doi:10.1371/journal.pone.0067961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asquith KL, Baleato RM, McLaughlin EA, Nixon B, Aitken RJ (2004) Tyrosine phosphorylation activates surface chaperones facilitating sperm-zona recognition. J Cell Sci 117(Pt 16):3645–3657. doi:10.1242/jcs.01214

    Article  CAS  PubMed  Google Scholar 

  • Audouard C, Christians E (2011) Hsp90beta1 knockout targeted to male germline: a mouse model for globozoospermia. Fertil Steril 95 (4):1475–7 e1–4. doi:10.1016/j.fertnstert.2010.12.006

  • Baker MA, Weinberg A, Hetherington L, Villaverde AI, Velkov T, Baell J, Gordon CP (2015) Defining the mechanisms by which the reactive oxygen species by-product, 4-hydroxynonenal, affects human sperm cell function. Biol Reprod 92(4):108. doi:10.1095/biolreprod.114.126680

    Article  PubMed  CAS  Google Scholar 

  • Balchin D, Hayer-Hartl M, Hartl FU (2016) In vivo aspects of protein folding and quality control. Science 353(6294):aac4354. doi:10.1126/science.aac4354

    Article  PubMed  CAS  Google Scholar 

  • Banerji J, Sands J, Strominger JL, Spies T (1990) A gene pair from the human major histocompatibility complex encodes large proline-rich proteins with multiple repeated motifs and a single ubiquitin-like domain. Proc Natl Acad Sci USA 87(6):2374–2378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beaupre CE, Tressler CJ, Beaupre SJ, Morgan JL, Bottje WG, Kirby JD (1997) Determination of testis temperature rhythms and effects of constant light on testicular function in the domestic fowl (Gallus domesticus). Biol Reprod 56(6):1570–1575

    Article  CAS  PubMed  Google Scholar 

  • Berruti G, Martegani E (2001) MSJ-1, a mouse testis-specific DnaJ protein, is highly expressed in haploid male germ cells and interacts with the testis-specific heat shock protein Hsp70-2. Biol Reprod 65(2):488–495

    Article  CAS  PubMed  Google Scholar 

  • Berruti G, Perego L, Borgonovo B, Martegani E (1998a) MSJ-1, a new member of the DNAJ family of proteins, is a male germ cell-specific gene product. Exp Cell Res 239(2):430–441. doi:10.1006/excr.1997.3879

    Article  CAS  PubMed  Google Scholar 

  • Berruti G, Perego L, Martegani E (1998b) Molecular cloning and developmental pattern of expression of MSJ-1, a new male germ cell-specific DNAJ homologue. Adv Exp Med Biol 444:145–150 discussion 151

    Article  CAS  PubMed  Google Scholar 

  • Bertelsen EB, Chang L, Gestwicki JE, Zuiderweg ER (2009) Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci USA 106(21):8471–8476. doi:10.1073/pnas.0903503106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonnycastle LL, Yu CE, Hunt CR, Trask BJ, Clancy KP, Weber JL, Patterson D, Schellenberg GD (1994) Cloning, sequencing, and mapping of the human chromosome 14 heat shock protein gene (HSPA2). Genomics 23(1):85–93. doi:10.1006/geno.1994.1462

    Article  CAS  PubMed  Google Scholar 

  • Boulanger J, Faulds D, Eddy EM, Lingwood CA (1995) Members of the 70 kDa heat shock protein family specifically recognize sulfoglycolipids: role in gamete recognition and mycoplasma-related infertility. J Cell Physiol 165(1):7–17. doi:10.1002/jcp.1041650103

    Article  CAS  PubMed  Google Scholar 

  • Bromfield EG, Nixon B (2013) The function of chaperone proteins in the assemblage of protein complexes involved in gamete adhesion and fusion processes. Reproduction 145(2):R31–R42. doi:10.1530/REP-12-0316

    Article  CAS  PubMed  Google Scholar 

  • Bromfield E, Aitken RJ, Nixon B (2015a) Novel characterization of the HSPA2-stabilizing protein BAG6 in human spermatozoa. Mol Hum Reprod 21(10):755–769. doi:10.1093/molehr/gav041

    Article  PubMed  Google Scholar 

  • Bromfield EG, Aitken RJ, Anderson AL, McLaughlin EA, Nixon B (2015b) The impact of oxidative stress on chaperone-mediated human sperm-egg interaction. Hum Reprod 30(11):2597–2613. doi:10.1093/humrep/dev214

    Article  PubMed  Google Scholar 

  • Bromfield EG, McLaughlin EA, Aitken RJ, Nixon B (2016) Heat Shock Protein member A2 forms a stable complex with angiotensin converting enzyme and protein disulfide isomerase A6 in human spermatozoa. Mol Hum Reprod 22(2):93–109. doi:10.1093/molehr/gav073

    Article  PubMed  Google Scholar 

  • Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125(3):443–451. doi:10.1016/j.cell.2006.04.014

    Article  CAS  PubMed  Google Scholar 

  • Burel C, Mezger V, Pinto M, Rallu M, Trigon S, Morange M (1992) Mammalian heat shock protein families. Expression and functions. Experientia 48(7):629–634

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32(11):1050–1060

    Article  CAS  PubMed  Google Scholar 

  • Cao W, Huang P, Zhang L, Wu HZ, Zhang J, Shi FX (2009) Acute heat stress increases HSP70 expression in the testis, epididymis and vas deferens of adult male mice. Zhonghua Nan Ke Xue 15(3):200–206

    CAS  PubMed  Google Scholar 

  • Carbone DL, Doorn JA, Petersen DR (2004) 4-Hydroxynonenal regulates 26S proteasomal degradation of alcohol dehydrogenase. Free Radic Biol Med 37(9):1430–1439. doi:10.1016/j.freeradbiomed.2004.07.016

    Article  CAS  PubMed  Google Scholar 

  • Carbone DL, Doorn JA, Kiebler Z, Ickes BR, Petersen DR (2005) Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease. J Pharmacol Exp Ther 315(1):8–15. doi:10.1124/jpet.105.088088

    Article  CAS  PubMed  Google Scholar 

  • Carmona E, Weerachatyanukul W, Soboloff T, Fluharty AL, White D, Promdee L, Ekker M, Berger T, Buhr M, Tanphaichitr N (2002) Arylsulfatase a is present on the pig sperm surface and is involved in sperm-zona pellucida binding. Dev Biol 247(1):182–196. doi:10.1006/dbio.2002.0690

    Article  CAS  PubMed  Google Scholar 

  • Cayli S, Jakab A, Ovari L, Delpiano E, Celik-Ozenci C, Sakkas D, Ward D, Huszar G (2003) Biochemical markers of sperm function: male fertility and sperm selection for ICSI. Reprod BioMed Online 7(4):462–468

    Article  CAS  PubMed  Google Scholar 

  • Cayli S, Sakkas D, Vigue L, Demir R, Huszar G (2004) Cellular maturity and apoptosis in human sperm: creatine kinase, caspase-3 and Bcl-XL levels in mature and diminished maturity sperm. Mol Hum Reprod 10(5):365–372. doi:10.1093/molehr/gah050

    Article  CAS  PubMed  Google Scholar 

  • Cedenho AP, Lima SB, Cenedeze MA, Spaine DM, Ortiz V, Oehninger S (2006) Oligozoospermia and heat-shock protein expression in ejaculated spermatozoa. Hum Reprod 21(7):1791–1794. doi:10.1093/humrep/del055

    Article  CAS  PubMed  Google Scholar 

  • Corduan A, Lecomte S, Martin C, Michel D, Desmots F (2009) Sequential interplay between BAG6 and HSP70 upon heat shock. Cell Mol Life Sci 66(11–12):1998–2004. doi:10.1007/s00018-009-9198-z

    Article  CAS  PubMed  Google Scholar 

  • Desmots F, Russell HR, Lee Y, Boyd K, McKinnon PJ (2005) The reaper-binding protein scythe modulates apoptosis and proliferation during mammalian development. Mol Cell Biol 25(23):10329–10337. doi:10.1128/MCB.25.23.10329-10337.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dix DJ, Allen JW, Collins BW, Mori C, Nakamura N, Poorman-Allen P, Goulding EH, Eddy EM (1996a) Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc Natl Acad Sci USA 93(8):3264–3268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dix DJ, Rosario-Herrle M, Gotoh H, Mori C, Goulding EH, Barrett CV, Eddy EM (1996b) Developmentally regulated expression of Hsp70-2 and a Hsp70-2/lacZ transgene during spermatogenesis. Dev Biol 174(2):310–321. doi:10.1006/dbio.1996.0076

    Article  CAS  PubMed  Google Scholar 

  • Dix DJ, Allen JW, Collins BW, Poorman-Allen P, Mori C, Blizard DR, Brown PR, Goulding EH, Strong BD, Eddy EM (1997) HSP70-2 is required for desynapsis of synaptonemal complexes during meiotic prophase in juvenile and adult mouse spermatocytes. Development 124(22):4595–4603

    CAS  PubMed  Google Scholar 

  • Doiguchi M, Kaneko T, Urasoko A, Nishitani H, Iida H (2007) Identification of a heat-shock protein Hsp40, DjB1, as an acrosome- and a tail-associated component in rodent spermatozoa. Mol Reprod Dev 74(2):223–232. doi:10.1002/mrd.20609

    Article  CAS  PubMed  Google Scholar 

  • Dun MD, Mitchell LA, Aitken RJ, Nixon B (2010) Sperm-zona pellucida interaction: molecular mechanisms and the potential for contraceptive intervention. Handb Exp Pharmacol 198:139–178. doi:10.1007/978-3-642-02062-9_9

    Article  CAS  Google Scholar 

  • Dun MD, Smith ND, Baker MA, Lin M, Aitken RJ, Nixon B (2011) The chaperonin containing TCP1 complex (CCT/TRiC) is involved in mediating sperm-oocyte interaction. J Biol Chem 286(42):36875–36887. doi:10.1074/jbc.M110.188888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dun MD, Aitken RJ, Nixon B (2012) The role of molecular chaperones in spermatogenesis and the post-testicular maturation of mammalian spermatozoa. Hum Reprod Update 18(4):420–435. doi:10.1093/humupd/dms009

    Article  PubMed  Google Scholar 

  • Eddy EM (1999) Role of heat shock protein HSP70-2 in spermatogenesis. Rev Reprod 4(1):23–30

    Article  CAS  PubMed  Google Scholar 

  • Ellis RJ (1990) The molecular chaperone concept. Semin Cell Biol 1(1):1–9

    CAS  PubMed  Google Scholar 

  • Ergur AR, Dokras A, Giraldo JL, Habana A, Kovanci E, Huszar G (2002) Sperm maturity and treatment choice of in vitro fertilization (IVF) or intracytoplasmic sperm injection: diminished sperm HspA2 chaperone levels predict IVF failure. Fertil Steril 77(5):910–918

    Article  PubMed  Google Scholar 

  • Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11(1):81–128

    Article  CAS  PubMed  Google Scholar 

  • Farout L, Mary J, Vinh J, Szweda LI, Friguet B (2006) Inactivation of the proteasome by 4-hydroxy-2-nonenal is site specific and dependant on 20S proteasome subtypes. Arch Biochem Biophys 453(1):135–142. doi:10.1016/j.abb.2006.02.003

    Article  CAS  PubMed  Google Scholar 

  • Feng HL, Sandlow JI, Sparks AE (2001) Decreased expression of the heat shock protein hsp70-2 is associated with the pathogenesis of male infertility. Fertil Steril 76(6):1136–1139

    Article  CAS  PubMed  Google Scholar 

  • Frost RJ, Hamra FK, Richardson JA, Qi X, Bassel-Duby R, Olson EN (2010) MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs. Proc Natl Acad Sci USA 107(26):11847–11852. doi:10.1073/pnas.1007158107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70(1):603–647

    Article  CAS  PubMed  Google Scholar 

  • Gallup GG (2009) On the origin of descended scrotal testicles: the activation hypothesis. Evol Psychol 7:517–526

    Article  Google Scholar 

  • Govin J, Caron C, Escoffier E, Ferro M, Kuhn L, Rousseaux S, Eddy EM, Garin J, Khochbin S (2006) Post-meiotic shifts in HSPA2/HSP70.2 chaperone activity during mouse spermatogenesis. J Biol Chem 281(49):37888–37892. doi:10.1074/jbc.M608147200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guan J, Yuan L (2008) A heat-shock protein 40, DNAJB13, is an axoneme-associated component in mouse spermatozoa. Mol Reprod Dev 75(9):1379–1386. doi:10.1002/mrd.20874

    Article  CAS  PubMed  Google Scholar 

  • Hafizur RM, Yano M, Gotoh T, Mori M, Terada K (2004) Modulation of chaperone activities of Hsp70 and Hsp70-2 by a mammalian DnaJ/Hsp40 homolog, DjA4. J Biochem 135(2):193–200

    Article  CAS  PubMed  Google Scholar 

  • Held T, Paprotta I, Khulan J, Hemmerlein B, Binder L, Wolf S, Schubert S, Meinhardt A, Engel W, Adham IM (2006) Hspa4l-deficient mice display increased incidence of male infertility and hydronephrosis development. Mol Cell Biol 26(21):8099–8108. doi:10.1128/MCB.01332-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Held T, Barakat AZ, Mohamed BA, Paprotta I, Meinhardt A, Engel W, Adham IM (2011) Heat-shock protein HSPA4 is required for progression of spermatogenesis. Reproduction 142(1):133–144. doi:10.1530/REP-11-0023

    Article  CAS  PubMed  Google Scholar 

  • Hermo L, Pelletier RM, Cyr DG, Smith CE (2010) Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes. Microsc Res Tech 73(4):241–278. doi:10.1002/jemt.20783

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Zhou Z, Huang X, Xu M, Lu L, Xu Z, Li J, Sha J (2004) Expression of a novel DnaJA1 alternative splicing in human testis and sperm. Int J Androl 27(6):343–349. doi:10.1111/j.1365-2605.2004.00492.x

    Article  CAS  PubMed  Google Scholar 

  • Huszar G, Sbracia M, Vigue L, Miller DJ, Shur BD (1997) Sperm plasma membrane remodeling during spermiogenetic maturation in men: relationship among plasma membrane beta 1,4-galactosyltransferase, cytoplasmic creatine phosphokinase, and creatine phosphokinase isoform ratios. Biol Reprod 56(4):1020–1024

    Article  CAS  PubMed  Google Scholar 

  • Huszar G, Stone K, Dix D, Vigue L (2000) Putative creatine kinase M-isoform in human sperm is identified as the 70-kilodalton heat shock protein HspA2. Biol Reprod 63(3):925–932

    Article  CAS  PubMed  Google Scholar 

  • Huszar G, Ozenci CC, Cayli S, Zavaczki Z, Hansch E, Vigue L (2003) Hyaluronic acid binding by human sperm indicates cellular maturity, viability, and unreacted acrosomal status. Fertil Steril 79(Suppl 3):1616–1624

    Article  PubMed  Google Scholar 

  • Huszar G, Ozkavukcu S, Jakab A, Celik-Ozenci C, Sati GL, Cayli S (2006) Hyaluronic acid binding ability of human sperm reflects cellular maturity and fertilizing potential: selection of sperm for intracytoplasmic sperm injection. Curr Opin Obstet Gynecol 18(3):260–267. doi:10.1097/01.gco.0000193018.98061.2f

    Article  PubMed  Google Scholar 

  • Huszar G, Jakab A, Sakkas D, Ozenci CC, Cayli S, Delpiano E, Ozkavukcu S (2007) Fertility testing and ICSI sperm selection by hyaluronic acid binding: clinical and genetic aspects. Reprod BioMed Online 14(5):650–663

    Article  PubMed  Google Scholar 

  • Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11(8):579–592. doi:10.1038/nrm2941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14(1):105–111. doi:10.1007/s12192-008-0068-7

    Article  CAS  PubMed  Google Scholar 

  • Kim B, Park K, Rhee K (2013a) Heat stress response of male germ cells. Cell Mol Life Sci 70(15):2623–2636. doi:10.1007/s00018-012-1165-4

    Article  CAS  PubMed  Google Scholar 

  • Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU (2013b) Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 82:323–355. doi:10.1146/annurev-biochem-060208-092442

    Article  CAS  PubMed  Google Scholar 

  • Kimura M, Kim E, Kang W, Yamashita M, Saigo M, Yamazaki T, Nakanishi T, Kashiwabara S, Baba T (2009) Functional roles of mouse sperm hyaluronidases, HYAL5 and SPAM1, in fertilization. Biol Reprod 81(5):939–947. doi:10.1095/biolreprod.109.078816

    Article  CAS  PubMed  Google Scholar 

  • Kityk R, Kopp J, Sinning I, Mayer MP (2012) Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones. Mol Cell 48(6):863–874. doi:10.1016/j.molcel.2012.09.023

    Article  CAS  PubMed  Google Scholar 

  • Kon Y, Endoh D (2001) Heat-shock resistance in experimental cryptorchid testis of mice. Mol Reprod Dev 58(2):216–222. doi:10.1002/1098-2795(200102)58:2<216::AID-MRD11>3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  • Kovanci E, Kovacs T, Moretti E, Vigue L, Bray-Ward P, Ward DC, Huszar G (2001) FISH assessment of aneuploidy frequencies in mature and immature human spermatozoa classified by the absence or presence of cytoplasmic retention. Hum Reprod 16(6):1209–1217

    Article  CAS  PubMed  Google Scholar 

  • Krawczyk Z, Szymik N, Wisniewski J (1987) Expression of hsp70-related gene in developing and degenerating rat testis. Mol Biol Rep 12(1):35–41

    Article  CAS  PubMed  Google Scholar 

  • Kuwabara N, Minami R, Yokota N, Matsumoto H, Senda T, Kawahara H, Kato R (2015) Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis. J Biol Chem 290(15):9387–9398. doi:10.1074/jbc.M114.631804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laufen T, Mayer MP, Beisel C, Klostermeier D, Mogk A, Reinstein J, Bukau B (1999) Mechanism of regulation of hsp70 chaperones by DnaJ cochaperones. Proc Natl Acad Sci USA 96(10):5452–5457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JG, Ye Y (2013) Bag6/Bat3/Scythe: a novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation. Bioessays 35(4):377–385. doi:10.1002/bies.201200159

    Article  CAS  PubMed  Google Scholar 

  • Li W, Liu G (2014) DNAJB13, a type II HSP40 family member, localizes to the spermatids and spermatozoa during mouse spermatogenesis. BMC Dev Biol 14:38. doi:10.1186/s12861-014-0038-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lima SB, Cenedeze MA, Bertolla RP, Filho PA, Oehninger S, Cedenho AP (2006) Expression of the HSPA2 gene in ejaculated spermatozoa from adolescents with and without varicocele. Fertil Steril 86(6):1659–1663. doi:10.1016/j.fertnstert.2006.05.030

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Hendrickson WA (2007) Insights into Hsp70 chaperone activity from a crystal structure of the yeast Hsp110 Sse1. Cell 131(1):106–120. doi:10.1016/j.cell.2007.08.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Xia J, Cho KH, Clapham DE, Ren D (2007) CatSperbeta, a novel transmembrane protein in the CatSper channel complex. J Biol Chem 282(26):18945–18952. doi:10.1074/jbc.M701083200

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Shi X, Bi Y, Qi L, Guo X, Wang L, Zhou Z, Sha J (2014) SHCBP1L, a conserved protein in mammals, is predominantly expressed in male germ cells and maintains spindle stability during meiosis in testis. Mol Hum Reprod 20(6):463–475. doi:10.1093/molehr/gau014

    Article  PubMed  CAS  Google Scholar 

  • Marques C, Pereira P, Taylor A, Liang JN, Reddy VN, Szweda LI, Shang F (2004) Ubiquitin-dependent lysosomal degradation of the HNE-modified proteins in lens epithelial cells. FASEB J 18(12):1424–1426. doi:10.1096/fj.04-1743fje

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin-Deleon PA (2011) Germ-cell hyaluronidases: their roles in sperm function. Int J Androl 34(5 Pt 2):e306–e318. doi:10.1111/j.1365-2605.2010.01138.x

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Heredia J, de Mateo S, Vidal-Taboada JM, Ballesca JL, Oliva R (2008) Identification of proteomic differences in asthenozoospermic sperm samples. Hum Reprod 23(4):783–791. doi:10.1093/humrep/den024

    Article  CAS  PubMed  Google Scholar 

  • Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62(6):670–684. doi:10.1007/s00018-004-4464-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer MP, Kityk R (2015) Insights into the molecular mechanism of allostery in Hsp70s. Front Mol Biosci 2:58. doi:10.3389/fmolb.2015.00058

    Article  PubMed  PubMed Central  Google Scholar 

  • Meccariello R, Cobellis G, Berruti G, Junier MP, Ceriani M, Boilee S, Pierantoni R, Fasano S (2002) Mouse sperm cell-specific DnaJ first homologue: an evolutionarily conserved protein for spermiogenesis. Biol Reprod 66(5):1328–1335

    Article  CAS  PubMed  Google Scholar 

  • Meccariello R, Chianese R, Ciaramella V, Fasano S, Pierantoni R (2014) Molecular chaperones, cochaperones, and ubiquitination/deubiquitination system: involvement in the production of high quality spermatozoa. Biomed Res Int 2014:561426. doi:10.1155/2014/561426

    Article  PubMed  PubMed Central  Google Scholar 

  • Mezquita B, Mezquita C, Mezquita J (1998) Marked differences between avian and mammalian testicular cells in the heat shock induction and polyadenylation of Hsp70 and ubiquitin transcripts. FEBS Lett 436(3):382–386

    Article  CAS  PubMed  Google Scholar 

  • Minami R, Hayakawa A, Kagawa H, Yanagi Y, Yokosawa H, Kawahara H (2010) BAG-6 is essential for selective elimination of defective proteasomal substrates. J Cell Biol 190(4):637–650. doi:10.1083/jcb.200908092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moazamian R, Polhemus A, Connaughton H, Fraser B, Whiting S, Gharagozloo P, Aitken RJ (2015) Oxidative stress and human spermatozoa: diagnostic and functional significance of aldehydes generated as a result of lipid peroxidation. Mol Hum Reprod 21(6):502–515. doi:10.1093/molehr/gav014

    Article  PubMed  Google Scholar 

  • Morgner N, Schmidt C, Beilsten-Edmands V, Ebong IO, Patel NA, Clerico EM, Kirschke E, Daturpalli S, Jackson SE, Agard D, Robinson CV (2015) Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90. Cell Rep 11(5):759–769. doi:10.1016/j.celrep.2015.03.063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori C, Nakamura N, Dix DJ, Fujioka M, Nakagawa S, Shiota K, Eddy EM (1997) Morphological analysis of germ cell apoptosis during postnatal testis development in normal and Hsp 70-2 knockout mice. Dev Dyn 208(1):125–136. doi:10.1002/(SICI)1097-0177(199701)208:1<125::AID-AJA12>3.0.CO;2-5

    Article  CAS  PubMed  Google Scholar 

  • Motiei M, Tavalaee M, Rabiei F, Hajihosseini R, Nasr-Esfahani MH (2013) Evaluation of HSPA2 in fertile and infertile individuals. Andrologia 45(1):66–72. doi:10.1111/j.1439-0272.2012.01315.x

    Article  CAS  PubMed  Google Scholar 

  • Murashov AK, Wolgemuth DJ (1996) Sense and antisense transcripts of the developmentally regulated murine hsp70.2 gene are expressed in distinct and only partially overlapping areas in the adult brain. Brain Res Mol Brain Res 37(1–2):85–95

    Article  CAS  PubMed  Google Scholar 

  • Naaby-Hansen S, Herr JC (2010) Heat shock proteins on the human sperm surface. J Reprod Immunol 84(1):32–40. doi:10.1016/j.jri.2009.09.006

    Article  CAS  PubMed  Google Scholar 

  • Nixon B, Aitken RJ (2009) The biological significance of detergent-resistant membranes in spermatozoa. J Reprod Immunol 83(1–2):8–13. doi:10.1016/j.jri.2009.06.258

    Article  CAS  PubMed  Google Scholar 

  • Nixon B, Asquith KL, John Aitken R (2005) The role of molecular chaperones in mouse sperm-egg interactions. Mol Cell Endocrinol 240(1–2):1–10. doi:10.1016/j.mce.2005.06.004

    Article  CAS  PubMed  Google Scholar 

  • Nixon B, Aitken RJ, McLaughlin EA (2007) New insights into the molecular mechanisms of sperm-egg interaction. Cell Mol Life Sci 64(14):1805–1823. doi:10.1007/s00018-007-6552-x

    Article  CAS  PubMed  Google Scholar 

  • Nixon B, Mitchell LA, Anderson AL, McLaughlin EA, O'Bryan MK, Aitken RJ (2011) Proteomic and functional analysis of human sperm detergent resistant membranes. J Cell Physiol 226(10):2651–2665. doi:10.1002/jcp.22615

    Article  CAS  PubMed  Google Scholar 

  • Nixon B, Bromfield EG, Dun MD, Redgrove KA, McLaughlin EA, Aitken RJ (2015) The role of the molecular chaperone heat shock protein A2 (HSPA2) in regulating human sperm-egg recognition. Asian J Androl 17(4):568–573. doi:10.4103/1008-682X.151395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O'Brien DA (1987) Stage-specific protein synthesis by isolated spermatogenic cells throughout meiosis and early spermiogenesis in the mouse. Biol Reprod 37(1):147–157

    Article  PubMed  Google Scholar 

  • Ohtsuka K, Hata M (2000) Molecular chaperone function of mammalian Hsp70 and Hsp40—a review. Int J Hyperth 16(3):231–245

    Article  CAS  Google Scholar 

  • Padhi A, Ghaly MM, Ma L (2016) Testis-enriched heat shock protein A2 (HSPA2): adaptive advantages of the birds with internal testes over the mammals with testicular descent. Sci Rep 6:18770. doi:10.1038/srep18770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pei Y, Wu Y, Qin Y (2012) Effects of chronic heat stress on the expressions of heat shock proteins 60, 70, 90, A2, and HSC70 in the rabbit testis. Cell Stress Chaperones 17(1):81–87. doi:10.1007/s12192-011-0287-1

    Article  CAS  PubMed  Google Scholar 

  • Pelham HR (1984) Hsp70 accelerates the recovery of nucleolar morphology after heat shock. EMBO J 3(13):3095–3100

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perales-Calvo J, Muga A, Moro F (2010) Role of DnaJ G/F-rich domain in conformational recognition and binding of protein substrates. J Biol Chem 285(44):34231–34239. doi:10.1074/jbc.M110.144642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perluigi M, Coccia R, Butterfield DA (2012) 4-Hydroxy-2-nonenal, a reactive product of lipid peroxidation, and neurodegenerative diseases: a toxic combination illuminated by redox proteomics studies. Antioxid Redox Signal 17(11):1590–1609. doi:10.1089/ars.2011.4406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Purandhar K, Jena PK, Prajapati B, Rajput P, Seshadri S (2014) Understanding the role of heat shock protein isoforms in male fertility, aging and apoptosis. World J Mens Health 32(3):123–132. doi:10.5534/wjmh.2014.32.3.123

    Article  PubMed  PubMed Central  Google Scholar 

  • Radons J (2016) The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones 21(3):379–404. doi:10.1007/s12192-016-0676-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redgrove KA, Anderson AL, Dun MD, McLaughlin EA, O'Bryan MK, Aitken RJ, Nixon B (2011) Involvement of multimeric protein complexes in mediating the capacitation-dependent binding of human spermatozoa to homologous zonae pellucidae. Dev Biol 356(2):460–474. doi:10.1016/j.ydbio.2011.05.674

    Article  CAS  PubMed  Google Scholar 

  • Redgrove KA, Nixon B, Baker MA, Hetherington L, Baker G, Liu DY, Aitken RJ (2012) The molecular chaperone HSPA2 plays a key role in regulating the expression of sperm surface receptors that mediate sperm-egg recognition. PLoS One 7(11):e50851. doi:10.1371/journal.pone.0050851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redgrove KA, Anderson AL, McLaughlin EA, O’Bryan MK, Aitken RJ, Nixon B (2013) Investigation of the mechanisms by which the molecular chaperone HSPA2 regulates the expression of sperm surface receptors involved in human sperm-oocyte recognition. Mol Hum Reprod 19(3):120–135. doi:10.1093/molehr/gas064

    Article  CAS  PubMed  Google Scholar 

  • Ritossa F (1996) Discovery of the heat shock response. Cell Stress Chaperones 1(2):97–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosario MO, Perkins SL, O’Brien DA, Allen RL, Eddy EM (1992) Identification of the gene for the developmentally expressed 70 kDa heat-shock protein (P70) of mouse spermatogenic cells. Dev Biol 150(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Rose GD, Fleming PJ, Banavar JR, Maritan A (2006) A backbone-based theory of protein folding. Proc Natl Acad Sci USA 103(45):16623–16633. doi:10.1073/pnas.0606843103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rudiger S, Germeroth L, Schneider-Mergener J, Bukau B (1997) Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. EMBO J 16(7):1501–1507. doi:10.1093/emboj/16.7.1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarbeng EB, Liu Q, Tian X, Yang J, Li H, Wong JL, Zhou L, Liu Q (2015) A functional DnaK dimer is essential for the efficient interaction with Hsp40 heat shock protein. J Biol Chem 290(14):8849–8862. doi:10.1074/jbc.M114.596288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sasaki T, Marcon E, McQuire T, Arai Y, Moens PB, Okada H (2008) Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis. J Cell Biol 182(3):449–458. doi:10.1083/jcb.200802113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scieglinska D, Krawczyk Z (2014) Expression, function, and regulation of the testis-enriched heat shock HSPA2 gene in rodents and humans. Cell Stress Chaperones. doi:10.1007/s12192-014-0548-x

    PubMed  PubMed Central  Google Scholar 

  • Shaha C, Tripathi R, Mishra DP (2010) Male germ cell apoptosis: regulation and biology. Philos Trans R Soc Lond Ser B Biol Sci 365(1546):1501–1515. doi:10.1098/rstb.2009.0124

    Article  CAS  Google Scholar 

  • Shiber A, Ravid T (2014) Chaperoning proteins for destruction: diverse roles of Hsp70 chaperones and their co-chaperones in targeting misfolded proteins to the proteasome. Biomolecules 4(3):704–724. doi:10.3390/biom4030704

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shringarpure R, Grune T, Sitte N, Davies KJ (2000) 4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease. Cell Mol Life Sci 57(12):1802–1809

    Article  CAS  PubMed  Google Scholar 

  • Son WY, Hwang SH, Han CT, Lee JH, Kim S, Kim YC (1999) Specific expression of heat shock protein HspA2 in human male germ cells. Mol Hum Reprod 5(12):1122–1126

    Article  CAS  PubMed  Google Scholar 

  • Son WY, Han CT, Hwang SH, Lee JH, Kim S, Kim YC (2000) Repression of hspA2 messenger RNA in human testes with abnormal spermatogenesis. Fertil Steril 73(6):1138–1144

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Noguchi S, Arakawa H, Tokida T, Hashimoto M, Satow Y (2010) Peptide-binding sites as revealed by the crystal structures of the human Hsp40 Hdj1 C-terminal domain in complex with the octapeptide from human Hsp70. Biochemistry 49(39):8577–8584. doi:10.1021/bi100876n

    Article  CAS  PubMed  Google Scholar 

  • Tantibhedhyangkul J, Weerachatyanukul W, Carmona E, Xu H, Anupriwan A, Michaud D, Tanphaichitr N (2002) Role of sperm surface arylsulfatase A in mouse sperm-zona pellucida binding. Biol Reprod 67(1):212–219

    Article  CAS  PubMed  Google Scholar 

  • Terada K, Yomogida K, Imai T, Kiyonari H, Takeda N, Kadomatsu T, Yano M, Aizawa S, Mori M (2005) A type I DnaJ homolog, DjA1, regulates androgen receptor signaling and spermatogenesis. EMBO J 24(3):611–622. doi:10.1038/sj.emboj.7600549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thress K, Song J, Morimoto RI, Kornbluth S (2001) Reversible inhibition of Hsp70 chaperone function by Scythe and Reaper. EMBO J 20(5):1033–1041. doi:10.1093/emboj/20.5.1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Timakov B, Zhang P (2001) The hsp60B gene of Drosophila melanogaster is essential for the spermatid individualization process. Cell Stress Chaperones 6(1):71–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uchida K (2003) 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res 42(4):318–343

    Article  CAS  PubMed  Google Scholar 

  • Uchida K, Stadtman ER (1993) Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase. A possible involvement of intra- and intermolecular cross-linking reaction. J Biol Chem 268(9):6388–6393

    CAS  PubMed  Google Scholar 

  • Waites GM (1991) Thermoregulation of the scrotum and testis: studies in animals and significance for man. Adv Exp Med Biol 286:9–17

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Dou X, Gu D, Shen C, Yao T, Nguyen V, Braunschweig C, Song Z (2012) 4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPARgamma and accelerating ubiquitin-proteasome degradation. Mol Cell Endocrinol 349(2):222–231. doi:10.1016/j.mce.2011.10.027

    Article  CAS  PubMed  Google Scholar 

  • Wang SH, Cheng CY, Tang PC, Chen CF, Chen HH, Lee YP, Huang SY (2013) Differential gene expressions in testes of L2 strain Taiwan country chicken in response to acute heat stress. Theriogenology 79 (2):374–82 e371–7. doi:10.1016/j.theriogenology.2012.10.010

  • Widlak W, Vydra N, Malusecka E, Dudaladava V, Winiarski B, Scieglinska D, Widlak P (2007) Heat shock transcription factor 1 down-regulates spermatocyte-specific 70 kDa heat shock protein expression prior to the induction of apoptosis in mouse testes. Genes Cells 12(4):487–499. doi:10.1111/j.1365-2443.2007.01069.x

    Article  CAS  PubMed  Google Scholar 

  • Wu A, Anupriwan A, Iamsaard S, Chakrabandhu K, Santos DC, Rupar T, Tsang BK, Carmona E, Tanphaichitr N (2007) Sperm surface arylsulfatase A can disperse the cumulus matrix of cumulus oocyte complexes. J Cell Physiol 213(1):201–211. doi:10.1002/jcp.21113

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Liu F, Srakaew N, Koppisetty C, Nyholm PG, Carmona E, Tanphaichitr N (2012) Sperm arylsulfatase A binds to mZP2 and mZP3 glycoproteins in a nonenzymatic manner. Reproduction 144(2):209–219. doi:10.1530/REP-11-0338

    Article  CAS  PubMed  Google Scholar 

  • Yang C, Miao S, Zong S, Koide SS, Wang L (2005a) Identification and characterization of rDJL, a novel member of the DnaJ protein family, in rat testis. FEBS Lett 579(25):5734–5740. doi:10.1016/j.febslet.2005.09.046

    Article  CAS  PubMed  Google Scholar 

  • Yang HM, Liu G, Nie ZY, Nie DS, Deng Y, Lu GX (2005b) Molecular cloning of a novel rat gene Tsarg1, a member of the DnaJ/HSP40 protein family. DNA Seq 16(3):166–172. doi:10.1080/10425170500129736

    Article  CAS  PubMed  Google Scholar 

  • Yerbury JJ, Ooi L, Dillin A, Saunders DN, Hatters DM, Beart PM, Cashman NR, Wilson MR, Ecroyd H (2016) Walking the tightrope: proteostasis and neurodegenerative disease. J Neurochem 137(4):489–505. doi:10.1111/jnc.13575

    Article  CAS  PubMed  Google Scholar 

  • Yu SS, Takenaka O (2003) Molecular cloning, structure, and testis-specific expression of MFSJ1, a member of the DNAJ protein family, in the Japanese monkey (Macaca fuscata). Biochem Biophys Res Commun 301(2):443–449

    Article  CAS  PubMed  Google Scholar 

  • Zakeri ZF, Wolgemuth DJ, Hunt CR (1988) Identification and sequence analysis of a new member of the mouse HSP70 gene family and characterization of its unique cellular and developmental pattern of expression in the male germ line. Mol Cell Biol 8(7):2925–2932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zakeri ZF, Welch WJ, Wolgemuth DJ (1990) Characterization and inducibility of hsp 70 proteins in the male mouse germ line. J Cell Biol 111(5 Pt 1):1785–1792

    Article  CAS  PubMed  Google Scholar 

  • Zhou XC, Han XB, Hu ZY, Zhou RJ, Liu YX (2001) Expression of Hsp70-2 in unilateral cryptorchid testis of rhesus monkey during germ cell apoptosis. Endocrine 16(2):89–95. doi:10.1385/ENDO:16:2:089

    Article  CAS  PubMed  Google Scholar 

  • Zhou C, Kang W, Baba T (2012) Functional characterization of double-knockout mouse sperm lacking SPAM1 and ACR or SPAM1 and PRSS21 in fertilization. J Reprod Dev 58(3):330–337

    Article  CAS  PubMed  Google Scholar 

  • Zhu D, Dix DJ, Eddy EM (1997) HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes. Development 124(15):3007–3014

    CAS  PubMed  Google Scholar 

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Nixon, B., Bromfield, E.G., Cui, J., De Iuliis, G.N. (2017). Heat Shock Protein A2 (HSPA2): Regulatory Roles in Germ Cell Development and Sperm Function. In: MacPhee, D. (eds) The Role of Heat Shock Proteins in Reproductive System Development and Function. Advances in Anatomy, Embryology and Cell Biology, vol 222. Springer, Cham. https://doi.org/10.1007/978-3-319-51409-3_4

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