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Small heat shock proteins: multifaceted proteins with important implications for life

  • Meeting Review
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world’s experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26–29 August 2018.

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References

  • Adhikari AS, Sridhar Rao K, Rangaraj N, Parnaik VK, Mohan Rao C (2004) Heat stress-induced localization of small heat shock proteins in mouse myoblasts: intranuclear lamin A/C speckles as target for alphaB-crystallin and Hsp25. Exp Cell Res 299:393–403

    Article  CAS  PubMed  Google Scholar 

  • Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC (2011) Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc 86:876–884

    Article  PubMed  PubMed Central  Google Scholar 

  • Alberti S (2017) Phase separation in biology. Curr Biol 27:R1097–R1102

    Article  CAS  PubMed  Google Scholar 

  • Alberti S, Mateju D, Mediani L, Carra S (2017) Granulostasis: protein quality control of RNP granules. Front Mol Neurosci 10:84

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Aquilina JA, Benesch JL, Ding LL, Yaron O, Horwitz J, Robinson CV (2004) Phosphorylation of alphaB-crystallin alters chaperone function through loss of dimeric substructure. J Biol Chem 279:28675–28680

    Article  CAS  PubMed  Google Scholar 

  • Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Furst DO, Saftig P, Saint R, Fleischmann BK et al (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20:143–148

    Article  CAS  PubMed  Google Scholar 

  • Arrigo AP (2000) sHsp as novel regulators of programmed cell death and tumorigenicity. Pathologie-biologie 48:280–288

    CAS  PubMed  Google Scholar 

  • Arrigo AP, Ducasse C (2002) Expression of the anti-apoptotic protein Hsp27 during both the keratinocyte differentiation and dedifferentiation of HaCat cells: expression linked to changes in intracellular protein organization? Exp Gerontol 37:1247–1255

    Article  CAS  PubMed  Google Scholar 

  • Arrigo AP, Gibert B (2012) HspB1 dynamic phospho-oligomeric structure dependent interactome as cancer therapeutic target. Curr Mol Med 12:1151–1163

    Article  CAS  PubMed  Google Scholar 

  • Arrigo AP, Gibert B (2014) HspB1, HspB5 and HspB4 in human cancers: potent oncogenic role of some of their client proteins. Cancers 6:333–365

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arrigo AP, Suhan JP, Welch WJ (1988) Dynamic changes in the structure and intracellular locale of the mammalian low-molecular-weight heat shock protein. Mol Cell Biol 8:5059–5071

    CAS  PubMed  PubMed Central  Google Scholar 

  • Avellaneda MJ, Koers EJ, Naqvi MM, Tans SJ (2017) The chaperone toolbox at the single-molecule level: from clamping to confining. Protein Sci 26:1291–1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Babu MM (2016) The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease. Biochem Soc Trans 44:1185–1200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balogi Z, Cheregi O, Giese KC, Juhasz K, Vierling E, Vass I, Vigh L, Horvath I (2008) A mutant small heat shock protein with increased thylakoid association provides an elevated resistance against UV-B damage in synechocystis 6803. J Biol Chem 283:22983–22991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banani SF, Lee HO, Hyman AA, Rosen MK (2017) Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18:285–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basha E, O’Neill H, Vierling E (2012) Small heat shock proteins and alpha-crystallins: dynamic proteins with flexible functions. Trends Biochem Sci 37:106–117

    Article  CAS  PubMed  Google Scholar 

  • Baughman HER, Clouser AF, Klevit RE, Nath A (2018) HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation. J Biol Chem 293:2687–2700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benjamin IJ, Shelton J, Garry DJ, Richardson JA (1997) Temporospatial expression of the small HSP/alpha B-crystallin in cardiac and skeletal muscle during mouse development. Dev Dyn 208:75–84

    Article  CAS  PubMed  Google Scholar 

  • Benn SC, Perrelet D, Kato AC, Scholz J, Decosterd I, Mannion RJ, Bakowska JC, Woolf CJ (2002) Hsp27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron 36:45–56

    Article  CAS  PubMed  Google Scholar 

  • Bouhy D, Juneja M, Katona I, Holmgren A, Asselbergh B, De Winter V, Hochepied T, Goossens S, Haigh JJ, Libert C et al (2018) A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8. Acta Neuropathol 135:131–148

    Article  CAS  PubMed  Google Scholar 

  • Bruey JM, Paul C, Fromentin A, Hilpert S, Arrigo AP, Solary E, Garrido C (2000) Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene 19:4855–4863

    Article  CAS  PubMed  Google Scholar 

  • Buchan JR, Kolaitis RM, Taylor JP, Parker R (2013) Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153:1461–1474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bult CJ, White O, Olsen GJ, Zhou L, Fleischmann RD, Sutton GG, Blake JA, FitzGerald LM, Clayton RA, Gocayne JD, Kerlavage AR, Dougherty BA, Tomb JF, Adams MD, Reich CI, Overbeek R, Kirkness EF, Weinstock KG, Merrick JM, Glodek A, Scott JL, Geoghagen NSM, Weidman JF, Fuhrmann JL, Nguyen D, Utterback TR, Kelley JM, Peterson JD, Sadow PW, Hanna MC, Cotton MD, Roberts KM, Hurst MA, Kaine BP, Borodovsky M, Klenk HP, Fraser CM, Smith HO, Woese CR, Venter JC (1996) Complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii. Science (New York, NY) 273:1058–1073

    Article  CAS  Google Scholar 

  • Candido EP (2002) The small heat shock proteins of the nematode Caenorhabditis elegans: structure, regulation and biology. Prog Mol Subcell Biol 28:61–78

    Article  CAS  PubMed  Google Scholar 

  • Carra S, Seguin SJ, Lambert H, Landry J (2008) HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J Biol Chem 283:1437–1444

    Article  CAS  PubMed  Google Scholar 

  • Carra S, Alberti S, Arrigo PA, Benesch JL, Benjamin IJ, Boelens W, Bartelt-Kirbach B, Brundel B, Buchner J, Bukau B et al (2017) The growing world of small heat shock proteins: from structure to functions. Cell Stress Chaperones 22:601–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caspers GJ, Leunissen JA, de Jong WW (1995) The expanding small heat-shock protein family, and structure predictions of the conserved “alpha-crystallin domain”. J Mol Evol 40:238–248

    Article  CAS  PubMed  Google Scholar 

  • Cheng G, Basha E, Wysocki VH, Vierling E (2008) Insights into small heat shock protein and substrate structure during chaperone action derived from hydrogen/deuterium exchange and mass spectrometry. J Biol Chem 283:26634–26642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choudhary, D, Mossa, A, Jadhav, M, Cecconi C (2019). Bio-Molecular Applications of Recent Developments in Optical Tweezers. Biomolecules 9(1). https://doi.org/10.3390/biom9010023

  • Clark AR, Vree Egberts W, Kondrat FDL, Hilton GR, Ray NJ, Cole AR, Carver JA, Benesch JLP, Keep NH, Boelens WC, Slingsby C (2018) Terminal regions confer plasticity to the tetrameric assembly of human HspB2 and HspB3. J Mol Biol 430:3297–3310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti C, de Biasi S, Poletti A (2010) The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet 19:3440–3456

    Article  CAS  PubMed  Google Scholar 

  • d’Ydewalle C, Krishnan J, Chiheb DM, Van Damme P, Irobi J, Kozikowski AP, Vanden Berghe P, Timmerman V, Robberecht W, Van Den Bosch L (2011) HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med 17:968–974

    Article  PubMed  CAS  Google Scholar 

  • Dabbaghizadeh A, Finet S, Morrow G, Moutaoufik MT, Tanguay RM (2017) Oligomeric structure and chaperone-like activity of Drosophila melanogaster mitochondrial small heat shock protein Hsp22 and arginine mutants in the alpha-crystallin domain. Cell Stress Chaperones 22:577–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dabbaghizadeh A, Morrow G, Amer YO, Chatelain EH, Pichaud N, Tanguay RM (2018) Identification of proteins interacting with the mitochondrial small heat shock protein Hsp22 of Drosophila melanogaster: implication in mitochondrial homeostasis. PLoS One 13:e0193771

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Delbecq SP, Klevit RE (2013) One size does not fit all: the oligomeric states of alphaB crystallin. FEBS Lett 587:1073–1080

    Article  CAS  PubMed  Google Scholar 

  • Delbecq SP, Rosenbaum JC, Klevit RE (2015) A mechanism of subunit recruitment in human small heat shock protein oligomers. Biochemistry 54:4276–4284

    Article  CAS  PubMed  Google Scholar 

  • den Engelsman J, Gerrits D, de Jong WW, Robbins J, Kato K, Boelens WC (2005) Nuclear import of {alpha}B-crystallin is phosphorylation-dependent and hampered by hyperphosphorylation of the myopathy-related mutant R120G. J Biol Chem 280:37139–37148

    Article  CAS  Google Scholar 

  • Dilly GF, Young CR, Lane WS, Pangilinan J, Girguis PR (2012) Exploring the limit of metazoan thermal tolerance via comparative proteomics: thermally induced changes in protein abundance by two hydrothermal vent polychaetes. Proc Biol Sci 279:3347–3356

    PubMed  PubMed Central  Google Scholar 

  • Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6:197–208

    Article  CAS  PubMed  Google Scholar 

  • Ecroyd H, Meehan S, Horwitz J, Aquilina JA, Benesch JL, Robinson CV, Macphee CE, Carver JA (2007) Mimicking phosphorylation of alphaB-crystallin affects its chaperone activity. Biochem J 401:129–141

    Article  CAS  PubMed  Google Scholar 

  • Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V et al (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36:602–606

    Article  CAS  PubMed  Google Scholar 

  • Eyles SJ, Gierasch LM (2010) Nature’s molecular sponges: small heat shock proteins grow into their chaperone roles. Proc Natl Acad Sci U S A 107:2727–2728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleckenstein T, Kastenmuller A, Stein ML, Peters C, Daake M, Krause M, Weinfurtner D, Haslbeck M, Weinkauf S, Groll M et al (2015) The chaperone activity of the developmental small heat shock protein Sip1 is regulated by pH-dependent conformational changes. Mol Cell 58:1067–1078

    Article  CAS  PubMed  Google Scholar 

  • Gamerdinger M, Kaya AM, Wolfrum U, Clement AM, Behl C (2011) BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep 12:149–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganassi M, Mateju D, Bigi I, Mediani L, Poser I, Lee HO, Seguin SJ, Morelli FF, Vinet J, Leo G, Pansarasa O, Cereda C, Poletti A, Alberti S, Carra S (2016) A surveillance function of the HSPB8-BAG3-HSP70 chaperone complex ensures stress granule integrity and dynamism. Mol Cell 63:796–810

    Article  CAS  PubMed  Google Scholar 

  • Ghaoui R, Palmio J, Brewer J, Lek M, Needham M, Evila A, Hackman P, Jonson PH, Penttila S, Vihola A et al (2016) Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology 86:391–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giese KC, Vierling E (2002) Changes in oligomerization are essential for the chaperone activity of a small heat shock protein in vivo and in vitro. J Biol Chem 277:46310–46318

    Article  CAS  PubMed  Google Scholar 

  • Giese KC, Basha E, Catague BY, Vierling E (2005) Evidence for an essential function of the N terminus of a small heat shock protein in vivo, independent of in vitro chaperone activity. Proc Natl Acad Sci U S A 102:18896–18901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grose JH, Langston K, Wang X, Squires S, Mustafi SB, Hayes W, Neubert J, Fischer SK, Fasano M, Saunders GM, Dai Q, Christians E, Lewandowski ED, Ping P, Benjamin IJ (2015) Characterization of the cardiac overexpression of HSPB2 reveals mitochondrial and myogenic roles supported by a cardiac HspB2 interactome. PLoS One 10:e0133994

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grousl T, Ungelenk S, Miller S, Ho CT, Khokhrina M, Mayer MP, Bukau B, Mogk A (2018) A prion-like domain in Hsp42 drives chaperone-facilitated aggregation of misfolded proteins. J Cell Biol 217:1269–1285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo H, Bai Y, Xu P, Hu Z, Liu L, Wang F, Jin G, Wang F, Deng Q, Tu Y, Feng M, Lu D, Shen H, Wu T (2010) Functional promoter -1271G>C variant of HSPB1 predicts lung cancer risk and survival. J Clin Oncol 28:1928–1935

    Article  CAS  PubMed  Google Scholar 

  • Gupte AA, Bomhoff GL, Geiger PC (2008) Age-related differences in skeletal muscle insulin signaling: the role of stress kinases and heat shock proteins. J Appl Physiol (1985) 105:839–848

    Article  CAS  Google Scholar 

  • Haslbeck M, Vierling E (2015) A first line of stress defense: small heat shock proteins and their function in protein homeostasis. J Mol Biol 427:1537–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haslbeck M, Peschek J, Buchner J, Weinkauf S (2016) Structure and function of alpha-crystallins: traversing from in vitro to in vivo. Biochim Biophys Acta 1860:149–166

    Article  CAS  PubMed  Google Scholar 

  • Haslbeck, M, Weinkauf, S, Buchner J (2018) Small heat shock proteins: Simplicity meets complexity. J Biol Chem https://doi.org/10.1074/jbc.REV118.002809

  • Healy TM, Tymchuk WE, Osborne EJ, Schulte PM (2010) Heat shock response of killifish (Fundulus heteroclitus): candidate gene and heterologous microarray approaches. Physiol Genomics 41:171–184

    Article  CAS  PubMed  Google Scholar 

  • Hilton GR, Lioe H, Stengel F, Baldwin AJ, Benesch JL (2012) Small heat-shock proteins: paramedics of the cell. Top Curr Chem 328:69–98

    Article  CAS  Google Scholar 

  • Hochberg GKA, Shepherd DA, Marklund EG, Santhanagoplan I, Degiacomi MT, Laganowsky A, Allison TM, Basha E, Marty MT, Galpin MR, Struwe WB, Baldwin AJ, Vierling E, Benesch JLP (2018) Structural principles that enable oligomeric small heat-shock protein paralogs to evolve distinct functions. Science (New York, NY) 359:930–935

    Article  CAS  Google Scholar 

  • Hong SW, Vierling E (2000) Mutants of Arabidopsis thaliana defective in the acquisition of tolerance to high temperature stress. Proc Natl Acad Sci U S A 97:4392–4397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, De Vriendt E, Jacobs A, Van Gerwen V et al (2004) Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 36:597–601

    Article  CAS  PubMed  Google Scholar 

  • Ishiwata T, Orosz A, Wang X, Mustafi SB, Pratt GW, Christians ES, Boudina S, Abel ED, Benjamin IJ (2012) HSPB2 is dispensable for the cardiac hypertrophic response but reduces mitochondrial energetics following pressure overload in mice. PLoS One 7:e42118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R (2016) ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164:487–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jana NR, Zemskov EA, Wang G, Nukina N (2001) Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 10:1049–1059

    Article  CAS  PubMed  Google Scholar 

  • Jaya N, Garcia V, Vierling E (2009) Substrate binding site flexibility of the small heat shock protein molecular chaperones. Proc Natl Acad Sci U S A 106:15604–15609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston CL, Marzano NR, van Oijen AM, Ecroyd H (2018) Using single-molecule approaches to understand the molecular mechanisms of heat-shock protein chaperone function. J Mol Biol 430:4525–4546

    Article  CAS  PubMed  Google Scholar 

  • Kamradt MC, Chen F, Sam S, Cryns VL (2002) The small heat shock protein alpha B-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation. J Biol Chem 277:38731–38736

    Article  CAS  PubMed  Google Scholar 

  • Kamradt MC, Lu M, Werner ME, Kwan T, Chen F, Strohecker A, Oshita S, Wilkinson JC, Yu C, Oliver PG, Duckett CS, Buchsbaum DJ, LoBuglio AF, Jordan VC, Cryns VL (2005) The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3. J Biol Chem 280:11059–11066

    Article  CAS  PubMed  Google Scholar 

  • Kedersha NL, Gupta M, Li W, Miller I, Anderson P (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol 147:1431–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KK, Kim R, Kim SH (1998) Crystal structure of a small heat-shock protein. Nature 394:595–599

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolb SJ, Snyder PJ, Poi EJ, Renard EA, Bartlett A, Gu S, Sutton S, Arnold WD, Freimer ML, Lawson VH, Kissel JT, Prior TW (2010) Mutant small heat shock protein B3 causes motor neuropathy: utility of a candidate gene approach. Neurology 74:502–506

    Article  CAS  PubMed  Google Scholar 

  • Lavoie JN, Gingras-Breton G, Tanguay RM, Landry J (1993) Induction of Chinese hamster HSP27 gene expression in mouse cells confers resistance to heat shock. HSP27 stabilization of the microfilament organization. J Biol Chem 268:3420–3429

    Article  CAS  PubMed  Google Scholar 

  • Lavoie JN, Lambert H, Hickey E, Weber LA, Landry J (1995) Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27. Mol Cell Biol 15:505–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Zhu X, Yu K, Jiang H, Zhang Y, Deng S, Cheng L, Liu X, Zhong J, Zhang X, He M, Chen W, Yuan J, Gao M, Bai Y, Han X, Liu B, Luo X, Mei W, He X, Sun S, Zhang L, Zeng H, Sun H, Liu C, Guo Y, Zhang B, Zhang Z, Huang J, Pan A, Yuan Y, Angileri F, Ming B, Zheng F, Zeng Q, Mao X, Peng Y, Mao Y, He P, Wang QK, Qi L, Hu FB, Liang L, Wu T (2017) Genome-wide analysis of DNA methylation and acute coronary syndrome. Circ Res 120:1754–1767

    Article  CAS  PubMed  Google Scholar 

  • Litt M, Kramer P, LaMorticella DM, Murphey W, Lovrien EW, Weleber RG (1998) Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Hum Mol Genet 7:471–474

    Article  CAS  PubMed  Google Scholar 

  • Lockwood BL, Sanders JG, Somero GN (2010) Transcriptomic responses to heat stress in invasive and native blue mussels (genus Mytilus): molecular correlates of invasive success. J Exp Biol 213:3548–3558

    Article  CAS  PubMed  Google Scholar 

  • Lockwood BL, Connor KM, Gracey AY (2015) The environmentally tuned transcriptomes of Mytilus mussels. J Exp Biol 218:1822–1833

    Article  PubMed  Google Scholar 

  • Lockwood BL, Julick CR, Montooth KL (2017) Maternal loading of a small heat shock protein increases embryo thermal tolerance in Drosophila melanogaster. J Exp Biol 220:4492–4501

    PubMed  PubMed Central  Google Scholar 

  • Mainz A, Peschek J, Stavropoulou M, Back KC, Bardiaux B, Asami S, Prade E, Peters C, Weinkauf S, Buchner J, Reif B (2015) The chaperone alphaB-crystallin uses different interfaces to capture an amorphous and an amyloid client. Nat Struct Mol Biol 22:898–905

    Article  CAS  PubMed  Google Scholar 

  • Maitre M, Weidmann S, Rieu A, Fenel D, Schoehn G, Ebel C, Coves J, Guzzo J (2012) The oligomer plasticity of the small heat-shock protein Lo18 from Oenococcus oeni influences its role in both membrane stabilization and protein protection. The Biochemical journal 444:97–104

    Article  CAS  PubMed  Google Scholar 

  • Mashaghi A, Kramer G, Bechtluft P, Zachmann-Brand B, Driessen AJ, Bukau B, Tans SJ (2013) Reshaping of the conformational search of a protein by the chaperone trigger factor. Nature 500:98–101

    Article  CAS  PubMed  Google Scholar 

  • Mateju D, Franzmann TM, Patel A, Kopach A, Boczek EE, Maharana S, Lee HO, Carra S, Hyman AA, Alberti S (2017) An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. EMBO J 36:1669–1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer FL, Wilson D, Jacobsen ID, Miramon P, Slesiona S, Bohovych IM, Brown AJ, Hube B (2012) Small but crucial: the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans. PLoS One 7:e38584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDonald ET, Bortolus M, Koteiche HA, McHaourab HS (2012) Sequence, structure, and dynamic determinants of Hsp27 (HspB1) equilibrium dissociation are encoded by the N-terminal domain. Biochemistry 51:1257–1268

    Article  CAS  PubMed  Google Scholar 

  • McHaourab HS, Dodson EK, Koteiche HA (2002) Mechanism of chaperone function in small heat shock proteins. Two-mode binding of the excited states of T4 lysozyme mutants by alphaA-crystallin. J Biol Chem 277:40557–40566

    Article  CAS  PubMed  Google Scholar 

  • McLoughlin F, Basha E, Fowler ME, Kim M, Bordowitz J, Katiyar-Agarwal S, Vierling E (2016) Class I and II small heat shock proteins together with HSP101 protect protein translation factors during heat stress. Plant Physiol 172:1221–1236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mogk A, Bukau B (2017) Role of sHsps in organizing cytosolic protein aggregation and disaggregation. Cell Stress Chaperones 22:493–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mogk A, Bukau B, Kampinga HH (2018) Cellular handling of protein aggregates by disaggregation machines. Mol Cell 69:214–226

    Article  CAS  PubMed  Google Scholar 

  • Morelli FF, Verbeek DS, Bertacchini J, Vinet J, Mediani L, Marmiroli S, Cenacchi G, Nasi M, De Biasi S, Brunsting JF et al (2017) Aberrant compartment formation by HSPB2 mislocalizes lamin A and compromises nuclear integrity and function. Cell Rep 20:2100–2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morrow G, Inaguma Y, Kato K, Tanguay RM (2000) The small heat shock protein Hsp22 of Drosophila melanogaster is a mitochondrial protein displaying oligomeric organization. J Biol Chem 275:31204–31210

    Article  CAS  PubMed  Google Scholar 

  • Morrow G, Samson M, Michaud S, Tanguay RM (2004) Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 18:598–599

    Article  CAS  PubMed  Google Scholar 

  • Mymrikov EV, Daake M, Richter B, Haslbeck M, Buchner J (2017) The chaperone activity and substrate spectrum of human small heat shock proteins. J Biol Chem 292:672–684

    Article  CAS  PubMed  Google Scholar 

  • Nam DE, Nam SH, Lee AJ, Hong YB, Choi BO, Chung KW (2018) Small heat shock protein B3 (HSPB3) mutation in an axonal Charcot-Marie-Tooth disease family. J Peripher Nerv Syst 23:60–66

    Article  CAS  PubMed  Google Scholar 

  • Nicholl ID, Quinlan RA (1994) Chaperone activity of alpha-crystallins modulates intermediate filament assembly. EMBO J 13:945–953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nover L, Scharf KD, Neumann D (1989) Cytoplasmic heat shock granules are formed from precursor particles and are associated with a specific set of mRNAs. Mol Cell Biol 9:1298–1308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oates ME, Romero P, Ishida T, Ghalwash M, Mizianty MJ, Xue B, Dosztanyi Z, Uversky VN, Obradovic Z, Kurgan L et al (2013) D(2)P(2): database of disordered protein predictions. Nucleic Acids Res 41:D508–D516

    Article  CAS  PubMed  Google Scholar 

  • Oya-Ito T, Naito Y, Takagi T, Handa O, Matsui H, Yamada M, Shima K, Yoshikawa T (2011) Heat-shock protein 27 (Hsp27) as a target of methylglyoxal in gastrointestinal cancer. Biochim Biophys Acta 1812:769–781

    Article  CAS  PubMed  Google Scholar 

  • Parcellier A, Brunet M, Schmitt E, Col E, Didelot C, Hammann A, Nakayama K, Nakayama KI, Khochbin S, Solary E, Garrido C (2006) HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells. FASEB J 20:1179–1181

    Article  CAS  PubMed  Google Scholar 

  • Park AM, Kanai K, Itoh T, Sato T, Tsukui T, Inagaki Y, Selman M, Matsushima K, Yoshie O (2016) Heat shock protein 27 plays a pivotal role in myofibroblast differentiation and in the development of bleomycin-induced pulmonary fibrosis. PLoS One 11:e0148998

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM, Pozniakovski A, Poser I, Maghelli N, Royer LA, Weigert M, Myers EW, Grill S, Drechsel D, Hyman AA, Alberti S (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–1077

    Article  CAS  PubMed  Google Scholar 

  • Perng MD, Cairns L, van den IP, Prescott A, Hutcheson AM, Quinlan RA (1999a) Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. J Cell Sci 112(Pt 13):2099–2112

    Article  CAS  PubMed  Google Scholar 

  • Perng MD, Muchowski PJ, van Den IP, Wu GJ, Hutcheson AM, Clark JI, Quinlan RA (1999b) The cardiomyopathy and lens cataract mutation in alphaB-crystallin alters its protein structure, chaperone activity, and interaction with intermediate filaments in vitro. J Biol Chem 274:33235–33243

    Article  CAS  PubMed  Google Scholar 

  • Peschek J, Braun N, Rohrberg J, Back KC, Kriehuber T, Kastenmuller A, Weinkauf S, Buchner J (2013) Regulated structural transitions unleash the chaperone activity of alphaB-crystallin. Proc Natl Acad Sci U S A 110:E3780–E3789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potenza E, Di Domenico T, Walsh I, Tosatto SC (2015) MobiDB 2.0: an improved database of intrinsically disordered and mobile proteins. Nucleic Acids Res 43:D315–D320

    Article  CAS  PubMed  Google Scholar 

  • Qian J, Ren X, Wang X, Zhang P, Jones WK, Molkentin JD, Fan GC, Kranias EG (2009) Blockade of Hsp20 phosphorylation exacerbates cardiac ischemia/reperfusion injury by suppressed autophagy and increased cell death. Circ Res 105:1223–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quinlan R, Van Den Ijssel P (1999) Fatal attraction: when chaperone turns harlot. Nat Med 5:25–26

    Article  CAS  PubMed  Google Scholar 

  • Reichmann D, Xu Y, Cremers CM, Ilbert M, Mittelman R, Fitzgerald MC, Jakob U (2012) Order out of disorder: working cycle of an intrinsically unfolded chaperone. Cell 148:947–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riback JA, Katanski CD, Kear-Scott JL, Pilipenko EV, Rojek AE, Sosnick TR, Drummond DA (2017) Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168:1028–1040 e1019

    Article  CAS  Google Scholar 

  • Richter K, Haslbeck M, Buchner J (2010) The heat shock response: life on the verge of death. Mol Cell 40:253–266

    Article  CAS  PubMed  Google Scholar 

  • Rosenbaum JC, Fredrickson EK, Oeser ML, Garrett-Engele CM, Locke MN, Richardson LA, Nelson ZW, Hetrick ED, Milac TI, Gottschling DE, Gardner RG (2011) Disorder targets misorder in nuclear quality control degradation: a disordered ubiquitin ligase directly recognizes its misfolded substrates. Mol Cell 41:93–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakamoto H, Mashima T, Yamamoto K, Tsuruo T (2002) Modulation of heat-shock protein 27 (Hsp27) anti-apoptotic activity by methylglyoxal modification. J Biol Chem 277:45770–45775

    Article  CAS  PubMed  Google Scholar 

  • Schon EA, Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70:1033–1053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schrepfer E, Scorrano L (2016) Mitofusins, from mitochondria to metabolism. Mol Cell 61:683–694

    Article  CAS  PubMed  Google Scholar 

  • Seguin SJ, Morelli FF, Vinet J, Amore D, De Biasi S, Poletti A, Rubinsztein DC, Carra S (2014) Inhibition of autophagy, lysosome and VCP function impairs stress granule assembly. Cell Death Differ 21:1838–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stromer T, Fischer E, Richter K, Haslbeck M, Buchner J (2004) Analysis of the regulation of the molecular chaperone Hsp26 by temperature-induced dissociation: the N-terminal domail is important for oligomer assembly and the binding of unfolding proteins. J Biol Chem 279:11222–11228

    Article  CAS  PubMed  Google Scholar 

  • Sudnitsyna MV, Mymrikov EV, Seit-Nebi AS, Gusev NB (2011) The role of intrinsically disordered regions in the structure and functioning of small heat shock proteins. Curr Protein Pept Sci 13:76–85

    Article  Google Scholar 

  • Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047

    Article  CAS  PubMed  Google Scholar 

  • Tanguay RM, Hightower LE (2015) In: Asea AAA, Calderwood SK (eds) The big book on small heat shock proteins, vol 8. Springer, Berlin

    Chapter  Google Scholar 

  • Taylor JP, Brown RH Jr, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539:197–206

    Article  PubMed  PubMed Central  Google Scholar 

  • Ungelenk S, Moayed F, Ho CT, Grousl T, Scharf A, Mashaghi A, Tans S, Mayer MP, Mogk A, Bukau B (2016) Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nat Commun 7:13673

    Article  PubMed  PubMed Central  Google Scholar 

  • van den IP, Wheelock R, Prescott A, Russell P, Quinlan RA (2003) Nuclear speckle localisation of the small heat shock protein alpha B-crystallin and its inhibition by the R120G cardiomyopathy-linked mutation. Exp Cell Res 287:249–261

    Article  CAS  Google Scholar 

  • Van Montfort R, Slingsby C, Vierling E (2001a) Structure and function of the small heat shock protein/alpha-crystallin family of molecular chaperones. Adv Protein Chem 59:105–156

    Article  PubMed  Google Scholar 

  • van Montfort RL, Basha E, Friedrich KL, Slingsby C, Vierling E (2001b) Crystal structure and assembly of a eukaryotic small heat shock protein. Nat Struct Biol 8:1025–1030

    Article  PubMed  CAS  Google Scholar 

  • van Rijk AE, Stege GJ, Bennink EJ, May A, Bloemendal H (2003) Nuclear staining for the small heat shock protein alphaB-crystallin colocalizes with splicing factor SC35. Eur J Cell Biol 82:361–368

    Article  PubMed  Google Scholar 

  • Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM et al (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20:92–95

    Article  CAS  PubMed  Google Scholar 

  • Wang F, Zhu J, Yao P, Li X, He M, Liu Y, Yuan J, Chen W, Zhou L, Min X, Fang W, Liang Y, Wang Y, Wei S, Liu J, Miao X, Lang M, Jiang X, Zhang P, Li D, Lu C, Wang X, Shi W, Zheng J, Guo H, Zhang X, Yang H, Hu FB, Wu T (2013) Cohort profile: the Dongfeng-Tongji cohort study of retired workers. Int J Epidemiol 42:731–740

    Article  PubMed  Google Scholar 

  • Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337:635–645

    Article  CAS  PubMed  Google Scholar 

  • Webster KA (2003) Serine phosphorylation and suppression of apoptosis by the small heat shock protein alphaB-crystallin. Circ Res 92:130–132

    Article  CAS  PubMed  Google Scholar 

  • Whiten DR, San Gil R, McAlary L, Yerbury JJ, Ecroyd H, Wilson MR (2016) Rapid flow cytometric measurement of protein inclusions and nuclear trafficking. Sci Rep 6:31138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young G, Hundt N, Cole D, Fineberg A, Andrecka J, Tyler A, Olerinyova A, Ansari A, Marklund EG, Collier MP, Chandler SA, Tkachenko O, Allen J, Crispin M, Billington N, Takagi Y, Sellers JR, Eichmann C, Selenko P, Frey L, Riek R, Galpin MR, Struwe WB, Benesch JLP, Kukura P (2018) Quantitative mass imaging of single biological macromolecules. Science (New York, NY) 360:423–427

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to the Cell Stress Society International (CSSI) for its financial support of the workshop. We thank the Fund for Scientific Research in Flanders-Belgium (FWO) for supporting the attendance at the workshop of PhD students, Elias Adriaenssens and Leen Vendredy.

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Authors and Affiliations

  1. Department of Biomedical, Metabolic and Neural Sciences, and Centre for Neuroscience and Nanotechnology, University of Modena and Reggio Emilia, via G. Campi 287, 41125, Modena, Italy

    Serena Carra

  2. Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany

    Simon Alberti

  3. Center for Molecular and Cellular Bioengineering (CMCB), Biotechnology Center (BIOTEC), Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany

    Simon Alberti

  4. Department of Chemistry, Physical and Theoretical Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK

    Justin L. P. Benesch

  5. Department of Biomolecular Chemistry, Institute of Molecules and Materials, Radboud University, NL-6500, Nijmegen, The Netherlands

    Wilbert Boelens

  6. Center for Integrated Protein Science Munich (CIPSM) and Department Chemie, Technische Universität München, D-85748, Garching, Germany

    Johannes Buchner

  7. Research School of Chemistry, The Australian National University, Acton, ACT, 2601, Australia

    John A. Carver

  8. Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, 41125, Modena, Italy

    Ciro Cecconi

  9. Center S3, CNR Institute Nanoscience, Via Campi 213/A, 41125, Modena, Italy

    Ciro Cecconi

  10. School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia

    Heath Ecroyd

  11. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia

    Heath Ecroyd

  12. Department of Biochemistry, School of Biology, Moscow State University, Moscow, Russian Federation, 117234

    Nikolai Gusev

  13. Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Storrs, CT, 06269-3125, USA

    Lawrence E. Hightower

  14. Department of Biochemistry, University of Washington, Seattle, WA, USA

    Rachel E. Klevit

  15. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Hyun O. Lee

  16. Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Abrahama 58, 80-307, Gdansk, Poland

    Krzysztof Liberek

  17. Department of Biology, University of Vermont, Burlington, VT, 05405, USA

    Brent Lockwood

  18. Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Univrsità degli Studi di Milano, Milan, Italy

    Angelo Poletti

  19. Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, 2610, Antwerp, Belgium

    Vincent Timmerman

  20. Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary

    Melinda E. Toth

  21. Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA, 01003, USA

    Elizabeth Vierling

  22. MOE Key Lab of Environment and Health, Tongji School of Public Health, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China

    Tangchun Wu

  23. Laboratory of Cell and Developmental Genetics, IBIS, and Department of Molecular Biology, Medical Biochemistry and Pathology, Medical School, Université Laval, QC, Québec, G1V 0A6, Canada

    Robert M. Tanguay

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  1. Serena Carra
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Correspondence to Serena Carra or Robert M. Tanguay.

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Carra, S., Alberti, S., Benesch, J.L.P. et al. Small heat shock proteins: multifaceted proteins with important implications for life. Cell Stress and Chaperones 24, 295–308 (2019). https://doi.org/10.1007/s12192-019-00979-z

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