Cellular and Molecular Life Sciences

, Volume 71, Issue 10, pp 1865–1879 | Cite as

Cellular maintenance of nuclear protein homeostasis

  • Pamela S. Gallagher
  • Michelle L. Oeser
  • Ayelet-chen Abraham
  • Daniel Kaganovich
  • Richard G. Gardner


The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. However, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin–proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.


Nucleus Chaperone Ubiquitin-protein ligase Ubiquitin Proteasome Unfolded protein response Misfolded protein Aggregation Inclusion Aggresome JUNQ 



We tried to cite all primary literature pertaining to nuclear PQC. We apologize to any colleagues if we unintentionally missed their studies. This work was supported by an NIH/NIA grant R01AG031136 (R.G.G.), an Ellison Medical Foundation New Scholar Award in Aging (R.G.G), an Israel Science Foundation Grant ISF 843/11 (D.K), a German–Israel Foundation Grant GIF I-1201-242.13/2012 (D.K.), an ERC-StG2013 337713 DarkSide grant (D.K.), and an American Federation for Aging Research grant (D.K.).


  1. 1.
    Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319:916–919PubMedGoogle Scholar
  2. 2.
    Wang SS, Wu JW, Yamamoto S, Liu HS (2008) Diseases of protein aggregation and the hunt for potential pharmacological agents. Biotechnol J 3:165–192PubMedGoogle Scholar
  3. 3.
    Kikis EA, Gidalevitz T, Morimoto RI (2010) Protein homeostasis in models of aging and age-related conformational disease. Adv Exp Med Biol 694:138–159PubMedCentralPubMedGoogle Scholar
  4. 4.
    Taylor RC, Dillin A (2011) Aging as an event of proteostasis collapse. Cold Spring Harb Perspect Biol 3:a004440Google Scholar
  5. 5.
    Voisine C, Pedersen JS, Morimoto RI (2010) Chaperone networks: tipping the balance in protein folding diseases. Neurobiol Dis 40:12–20PubMedCentralPubMedGoogle Scholar
  6. 6.
    Chen B, Retzlaff M, Roos T, Frydman J (2011) Cellular strategies of protein quality control. Cold Spring Harb Perspect Biol 3:a004374PubMedCentralPubMedGoogle Scholar
  7. 7.
    Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332PubMedGoogle Scholar
  8. 8.
    Fredrickson EK, Gardner RG (2012) Selective destruction of abnormal proteins by ubiquitin-mediated protein quality control degradation. Semin Cell Dev Biol 23:530–537PubMedCentralPubMedGoogle Scholar
  9. 9.
    Sridhar S, Botbol Y, Macian F, Cuervo AM (2012) Autophagy and disease: always two sides to a problem. J Pathol 226:255–273PubMedPubMedCentralGoogle Scholar
  10. 10.
    Arndt V, Rogon C, Hohfeld J (2007) To be, or not to be–molecular chaperones in protein degradation. Cell Mol Life Sci 64:2525–2541PubMedGoogle Scholar
  11. 11.
    Wickner S, Maurizi MR, Gottesman S (1999) Posttranslational quality control: folding, refolding, and degrading proteins. Science 286:1888–1893PubMedGoogle Scholar
  12. 12.
    Gardner BM, Pincus D, Gotthardt K, Gallagher CM, Walter P (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol 5:a013169PubMedGoogle Scholar
  13. 13.
    Haynes CM, Fiorese CJ, Lin YF (2013) Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond. Trends Cell Biol 23:311–318Google Scholar
  14. 14.
    Woulfe J (2008) Nuclear bodies in neurodegenerative disease. Biochim Biophys Acta 1783:2195–2206PubMedGoogle Scholar
  15. 15.
    Ross CA (2002) Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron 35:819–822PubMedGoogle Scholar
  16. 16.
    Amiel J, Trochet D, Clement-Ziza M, Munnich A, Lyonnet S (2004) Polyalanine expansions in human. Hum Mol Genet 13 Spec No 2: R235–R243Google Scholar
  17. 17.
    David A, Dolan BP, Hickman HD, Knowlton JJ, Clavarino G, Pierre P, Bennink JR, Yewdell JW (2012) Nuclear translation visualized by ribosome-bound nascent chain puromycylation. J Cell Biol 197:45–57PubMedCentralPubMedGoogle Scholar
  18. 18.
    Iborra FJ, Jackson DA, Cook PR (2001) Coupled transcription and translation within nuclei of mammalian cells. Science 293:1139–1142PubMedGoogle Scholar
  19. 19.
    Iborra FJ, Escargueil AE, Kwek KY, Akoulitchev A, Cook PR (2004) Molecular cross-talk between the transcription, translation, and nonsense-mediated decay machineries. J Cell Sci 117:899–906PubMedGoogle Scholar
  20. 20.
    Iborra FJ, Jackson DA, Cook PR (2004) The case for nuclear translation. J Cell Sci 117:5713–5720PubMedGoogle Scholar
  21. 21.
    Dahlberg JE, Lund E, Goodwin EB (2003) Nuclear translation: what is the evidence? RNA 9:1–8PubMedCentralPubMedGoogle Scholar
  22. 22.
    Pederson T (2013) The persistent plausibility of protein synthesis in the nucleus: process, palimpsest or pitfall? Curr Opin Cell Biol 25:520–521PubMedGoogle Scholar
  23. 23.
    Nathanson L, Xia T, Deutscher MP (2003) Nuclear protein synthesis: a re-evaluation. RNA 9:9–13PubMedCentralPubMedGoogle Scholar
  24. 24.
    Dahlberg J, Lund E (2012) Nuclear translation or nuclear peptidyl transferase? Nucleus 3:320–321PubMedGoogle Scholar
  25. 25.
    Grossman E, Medalia O, Zwerger M (2012) Functional architecture of the nuclear pore complex. Annu Rev Biophys 41:557–584PubMedGoogle Scholar
  26. 26.
    Pante N, Kann M (2002) Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell 13:425–434PubMedCentralPubMedGoogle Scholar
  27. 27.
    Dudek J, Rehling P, van der Laan M (2013) Mitochondrial protein import: common principles and physiological networks. Biochim Biophys Acta 1833:274–285PubMedGoogle Scholar
  28. 28.
    Johnson N, Powis K, High S (2012) Post-translational translocation into the endoplasmic reticulum. Biochim Biophys Acta 1833:2403–2409Google Scholar
  29. 29.
    Guerriero CJ, Weiberth KF, Brodsky JL (2013) Hsp70 targets a cytoplasmic quality control substrate to the San1p ubiquitin ligase. J Biol Chem 288:18506–18520PubMedGoogle Scholar
  30. 30.
    Heck JW, Cheung SK, Hampton RY (2010) Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proc Natl Acad Sci USA 107:1106–1111PubMedCentralPubMedGoogle Scholar
  31. 31.
    Park SH, Kukushkin Y, Gupta R, Chen T, Konagai A, Hipp MS, Hayer-Hartl M, Hartl FU (2013) PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone. Cell 154:134–145PubMedGoogle Scholar
  32. 32.
    Prasad R, Kawaguchi S, Ng DT (2010) A nucleus-based quality control mechanism for cytosolic proteins. Mol Biol Cell 21:2117–2127PubMedCentralPubMedGoogle Scholar
  33. 33.
    Prasad R, Kawaguchi S, Ng DT (2012) Biosynthetic mode can determine the mechanism of protein quality control. Biochem Biophys Res Commun 425:689–695PubMedGoogle Scholar
  34. 34.
    Summers DW, Wolfe KJ, Ren HY, Cyr DM (2013) The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein. PLoS ONE 8:e52099PubMedCentralPubMedGoogle Scholar
  35. 35.
    Wojcik C, DeMartino GN (2003) Intracellular localization of proteasomes. Int J Biochem Cell Biol 35:579–589PubMedGoogle Scholar
  36. 36.
    D’Angelo MA, Raices M, Panowski SH, Hetzer MW (2009) Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell 136:284–295PubMedCentralPubMedGoogle Scholar
  37. 37.
    Arrasate M, Finkbeiner S (2012) Protein aggregates in Huntington’s disease. Exp Neurol 238:1–11PubMedCentralPubMedGoogle Scholar
  38. 38.
    DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA et al (1995) Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14:1075–1081PubMedGoogle Scholar
  39. 39.
    DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993PubMedGoogle Scholar
  40. 40.
    Peters MF, Nucifora FC Jr, Kushi J, Seaman HC, Cooper JK, Herring WJ, Dawson VL, Dawson TM, Ross CA (1999) Nuclear targeting of mutant Huntingtin increases toxicity. Mol Cell Neurosci 14:121–128PubMedGoogle Scholar
  41. 41.
    Schilling G, Savonenko AV, Klevytska A, Morton JL, Tucker SM, Poirier M, Gale A, Chan N, Gonzales V, Slunt HH, Coonfield ML, Jenkins NA, Copeland NG, Ross CA, Borchelt DR (2004) Nuclear-targeting of mutant huntingtin fragments produces Huntington’s disease-like phenotypes in transgenic mice. Hum Mol Genet 13:1599–1610PubMedGoogle Scholar
  42. 42.
    Shen Y, Peterson AS (2009) Atrophins’ emerging roles in development and neurodegenerative disease. Cell Mol Life Sci 66:437–446PubMedGoogle Scholar
  43. 43.
    Katsuno M, Tanaka F, Adachi H, Banno H, Suzuki K, Watanabe H, Sobue G (2012) Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA). Prog Neurobiol 99:246–256PubMedGoogle Scholar
  44. 44.
    Brais B (2009) Oculopharyngeal muscular dystrophy: a polyalanine myopathy. Curr Neurol Neurosci Rep 9:76–82PubMedGoogle Scholar
  45. 45.
    Guigas G, Kalla C, Weiss M (2007) The degree of macromolecular crowding in the cytoplasm and nucleoplasm of mammalian cells is conserved. FEBS Lett 581:5094–5098PubMedGoogle Scholar
  46. 46.
    Guigas G, Kalla C, Weiss M (2007) Probing the nanoscale viscoelasticity of intracellular fluids in living cells. Biophys J 93:316–323PubMedCentralPubMedGoogle Scholar
  47. 47.
    Clapier CR, Cairns BR (2009) The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273–304PubMedGoogle Scholar
  48. 48.
    Lempiainen H, Shore D (2009) Growth control and ribosome biogenesis. Curr Opin Cell Biol 21:855–863PubMedGoogle Scholar
  49. 49.
    Morris GE (2008) The Cajal body. Biochim Biophys Acta 1783:2108–2115PubMedGoogle Scholar
  50. 50.
    Lallemand-Breitenbach V, de The H (2010) PML nuclear bodies. Cold Spring Harb Perspect Biol 2:a000661PubMedCentralPubMedGoogle Scholar
  51. 51.
    Dittmer TA, Misteli T (2011) The lamin protein family. Genome Biol 12:222PubMedCentralPubMedGoogle Scholar
  52. 52.
    Schreiber KH, Kennedy BK (2013) When lamins go bad: nuclear structure and disease. Cell 152:1365–1375PubMedCentralPubMedGoogle Scholar
  53. 53.
    Ehrlich ME (2012) Huntington’s disease and the striatal medium spiny neuron: cell-autonomous and non-cell-autonomous mechanisms of disease. Neurotherapeutics 9:270–284PubMedCentralPubMedGoogle Scholar
  54. 54.
    Desplats PA, Kass KE, Gilmartin T, Stanwood GD, Woodward EL, Head SR, Sutcliffe JG, Thomas EA (2006) Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease. J Neurochem 96:743–757PubMedGoogle Scholar
  55. 55.
    Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Ulrich Hartl F (2013) Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 82:323–355PubMedGoogle Scholar
  56. 56.
    Kriegenburg F, Ellgaard L, Hartmann-Petersen R (2012) Molecular chaperones in targeting misfolded proteins for ubiquitin-dependent degradation. FEBS J 279:532–542PubMedGoogle Scholar
  57. 57.
    Kodiha M, Chu A, Lazrak O, Stochaj U (2005) Stress inhibits nucleocytoplasmic shuttling of heat shock protein hsc70. Am J Physiol Cell Physiol 289:C1034–C1041PubMedGoogle Scholar
  58. 58.
    Welch WJ, Feramisco JR (1984) Nuclear and nucleolar localization of the 72,000-dalton heat shock protein in heat-shocked mammalian cells. J Biol Chem 259:4501–4513PubMedGoogle Scholar
  59. 59.
    Velazquez JM, Lindquist S (1984) hsp70: nuclear concentration during environmental stress and cytoplasmic storage during recovery. Cell 36:655–662PubMedGoogle Scholar
  60. 60.
    Pelham HR (1984) Hsp70 accelerates the recovery of nucleolar morphology after heat shock. EMBO J 3:3095–3100PubMedCentralPubMedGoogle Scholar
  61. 61.
    Lamian V, Small GM, Feldherr CM (1996) Evidence for the existence of a novel mechanism for the nuclear import of Hsc70. Exp Cell Res 228:84–91PubMedGoogle Scholar
  62. 62.
    Kose S, Furuta M, Imamoto N (2012) Hikeshi, a nuclear import carrier for Hsp70s, protects cells from heat shock-induced nuclear damage. Cell 149:578–589PubMedGoogle Scholar
  63. 63.
    Imamoto N, Kose S (2012) Heat-shock stress activates a novel nuclear import pathway mediated by Hikeshi. Nucleus 3:422–428PubMedCentralPubMedGoogle Scholar
  64. 64.
    Quan X, Rassadi R, Rabie B, Matusiewicz N, Stochaj U (2004) Regulated nuclear accumulation of the yeast hsp70 Ssa4p in ethanol-stressed cells is mediated by the N-terminal domain, requires the nuclear carrier Nmd5p and protein kinase C. FASEB J 18:899–901PubMedGoogle Scholar
  65. 65.
    Quan X, Tsoulos P, Kuritzky A, Zhang R, Stochaj U (2006) The carrier Msn5p/Kap142p promotes nuclear export of the hsp70 Ssa4p and relocates in response to stress. Mol Microbiol 62:592–609PubMedGoogle Scholar
  66. 66.
    Chughtai ZS, Rassadi R, Matusiewicz N, Stochaj U (2001) Starvation promotes nuclear accumulation of the hsp70 Ssa4p in yeast cells. J Biol Chem 276:20261–20266PubMedGoogle Scholar
  67. 67.
    Kawai R, Fujita K, Iwahashi H, Komatsu Y (1999) Direct evidence for the intracellular localization of Hsp104 in Saccharomyces cerevisiae by immunoelectron microscopy. Cell Stress Chaperones 4:46–53PubMedCentralPubMedGoogle Scholar
  68. 68.
    Tkach JM, Glover JR (2008) Nucleocytoplasmic trafficking of the molecular chaperone Hsp104 in unstressed and heat-shocked cells. Traffic 9:39–56PubMedGoogle Scholar
  69. 69.
    Parsell DA, Kowal AS, Singer MA, Lindquist S (1994) Protein disaggregation mediated by heat-shock protein Hsp104. Nature 372:475–478PubMedGoogle Scholar
  70. 70.
    Willsie JK, Clegg JS (2002) Small heat shock protein p26 associates with nuclear lamins and HSP70 in nuclei and nuclear matrix fractions from stressed cells. J Cell Biochem 84:601–614PubMedGoogle Scholar
  71. 71.
    Rossi JM, Lindquist S (1989) The intracellular location of yeast heat-shock protein 26 varies with metabolism. J Cell Biol 108:425–439PubMedGoogle Scholar
  72. 72.
    Kodiha M, Chu A, Matusiewicz N, Stochaj U (2004) Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress. Cell Death Differ 11:862–874PubMedGoogle Scholar
  73. 73.
    Czubryt MP, Austria JA, Pierce GN (2000) Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2. J Cell Biol 148:7–16PubMedCentralPubMedGoogle Scholar
  74. 74.
    Miyamoto Y, Saiwaki T, Yamashita J, Yasuda Y, Kotera I, Shibata S, Shigeta M, Hiraoka Y, Haraguchi T, Yoneda Y (2004) Cellular stresses induce the nuclear accumulation of importin alpha and cause a conventional nuclear import block. J Cell Biol 165:617–623PubMedCentralPubMedGoogle Scholar
  75. 75.
    Furuta M, Kose S, Koike M, Shimi T, Hiraoka Y, Yoneda Y, Haraguchi T, Imamoto N (2004) Heat-shock induced nuclear retention and recycling inhibition of importin alpha. Genes Cells 9:429–441PubMedGoogle Scholar
  76. 76.
    Kodiha M, Tran D, Qian C, Morogan A, Presley JF, Brown CM, Stochaj U (2008) Oxidative stress mislocalizes and retains transport factor importin-alpha and nucleoporins Nup153 and Nup88 in nuclei where they generate high molecular mass complexes. Biochim Biophys Acta 1783:405–418PubMedGoogle Scholar
  77. 77.
    Yasuda Y, Miyamoto Y, Saiwaki T, Yoneda Y (2006) Mechanism of the stress-induced collapse of the Ran distribution. Exp Cell Res 312:512–520PubMedGoogle Scholar
  78. 78.
    Kelley JB, Paschal BM (2007) Hyperosmotic stress signaling to the nucleus disrupts the Ran gradient and the production of RanGTP. Mol Biol Cell 18:4365–4376PubMedCentralPubMedGoogle Scholar
  79. 79.
    Crampton N, Kodiha M, Shrivastava S, Umar R, Stochaj U (2009) Oxidative stress inhibits nuclear protein export by multiple mechanisms that target FG nucleoporins and Crm1. Mol Biol Cell 20:5106–5116PubMedCentralPubMedGoogle Scholar
  80. 80.
    Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, Wanker EE (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393–1407PubMedCentralPubMedGoogle Scholar
  81. 81.
    Abel A, Walcott J, Woods J, Duda J, Merry DE (2001) Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 10:107–116PubMedGoogle Scholar
  82. 82.
    Jana NR, Tanaka M, Wang G, Nukina N (2000) Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum Mol Genet 9:2009–2018PubMedGoogle Scholar
  83. 83.
    Bailey CK, Andriola IF, Kampinga HH, Merry DE (2002) Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum Mol Genet 11:515–523PubMedGoogle Scholar
  84. 84.
    Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G (2003) Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J Neurosci 23:2203–2211PubMedGoogle Scholar
  85. 85.
    Ishihara K, Yamagishi N, Saito Y, Adachi H, Kobayashi Y, Sobue G, Ohtsuka K, Hatayama T (2003) Hsp105alpha suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. J Biol Chem 278:25143–25150PubMedGoogle Scholar
  86. 86.
    Latouche M, Fragner P, Martin E, El Hachimi KH, Zander C, Sittler A, Ruberg M, Brice A, Stevanin G (2006) Polyglutamine and polyalanine expansions in ataxin7 result in different types of aggregation and levels of toxicity. Mol Cell Neurosci 31:438–445PubMedGoogle Scholar
  87. 87.
    Janer A, Martin E, Muriel MP, Latouche M, Fujigasaki H, Ruberg M, Brice A, Trottier Y, Sittler A (2006) PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins. J Cell Biol 174:65–76PubMedCentralPubMedGoogle Scholar
  88. 88.
    Seidel K, Meister M, Dugbartey GJ, Zijlstra MP, Vinet J, Brunt ER, van Leeuwen FW, Rub U, Kampinga HH, den Dunnen WF (2012) Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3). Neuropathol Appl Neurobiol 38:548–558PubMedGoogle Scholar
  89. 89.
    Bao YP, Cook LJ, O’Donovan D, Uyama E, Rubinsztein DC (2002) Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy. J Biol Chem 277:12263–12269PubMedGoogle Scholar
  90. 90.
    Corbeil-Girard LP, Klein AF, Sasseville AM, Lavoie H, Dicaire MJ, Saint-Denis A, Page M, Duranceau A, Codere F, Bouchard JP, Karpati G, Rouleau GA, Massie B, Langelier Y, Brais B (2005) PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in oculopharyngeal muscular dystrophy nuclear inclusions. Neurobiol Dis 18:551–567PubMedGoogle Scholar
  91. 91.
    Chartier A, Benoit B, Simonelig M (2006) A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1. EMBO J 25:2253–2262PubMedCentralPubMedGoogle Scholar
  92. 92.
    Tavanez JP, Bengoechea R, Berciano MT, Lafarga M, Carmo-Fonseca M, Enguita FJ (2009) Hsp70 chaperones and type I PRMTs are sequestered at intranuclear inclusions caused by polyalanine expansions in PABPN1. PLoS ONE 4:e6418PubMedCentralPubMedGoogle Scholar
  93. 93.
    Fu L, Gao YS, Tousson A, Shah A, Chen TL, Vertel BM, Sztul E (2005) Nuclear aggresomes form by fusion of PML-associated aggregates. Mol Biol Cell 16:4905–4917PubMedCentralPubMedGoogle Scholar
  94. 94.
    Fu L, Gao YS, Sztul E (2005) Transcriptional repression and cell death induced by nuclear aggregates of non-polyglutamine protein. Neurobiol Dis 20:656–665PubMedCentralPubMedGoogle Scholar
  95. 95.
    Moran DM, Shen H, Maki CG (2009) Puromycin-based vectors promote a ROS-dependent recruitment of PML to nuclear inclusions enriched with HSP70 and Proteasomes. BMC Cell Biol 10:32PubMedCentralPubMedGoogle Scholar
  96. 96.
    Ciechanover A (2012) Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Neurodegener Dis 10:7–22PubMedGoogle Scholar
  97. 97.
    Finley D, Ulrich HD, Sommer T, Kaiser P (2012) The ubiquitin-proteasome system of Saccharomyces cerevisiae. Genetics 192:319–360PubMedCentralPubMedGoogle Scholar
  98. 98.
    Dasgupta A, Ramsey KL, Smith JS, Auble DT (2004) Sir antagonist 1 (San1) is a ubiquitin ligase. J Biol Chem 279:26830–26838PubMedGoogle Scholar
  99. 99.
    Gardner RG, Nelson ZW, Gottschling DE (2005) Degradation-mediated protein quality control in the nucleus. Cell 120:803–815PubMedGoogle Scholar
  100. 100.
    Evans DR, Brewster NK, Xu Q, Rowley A, Altheim BA, Johnston GC, Singer RA (1998) The yeast protein complex containing cdc68 and pob3 mediates core-promoter repression through the cdc68 N-terminal domain. Genetics 150:1393–1405PubMedCentralPubMedGoogle Scholar
  101. 101.
    Estruch F, Peiro-Chova L, Gomez-Navarro N, Durban J, Hodge C, Del Olmo M, Cole CN (2009) A genetic screen in Saccharomyces cerevisiae identifies new genes that interact with me67-5, a temperature-sensitive allele of the gene encoding the mRNA export receptor. Mol Genet Genomics 281:125–134PubMedGoogle Scholar
  102. 102.
    Lewis MJ, Pelham HR (2009) Inefficient quality control of thermosensitive proteins on the plasma membrane. PLoS ONE 4:e5038PubMedCentralPubMedGoogle Scholar
  103. 103.
    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 41:93–106PubMedCentralPubMedGoogle Scholar
  104. 104.
    Fredrickson EK, Gallagher PS, Clowes Candadai SV, Gardner RG (2013) Substrate recognition in nuclear protein quality control degradation is governed by exposed hydrophobicity that correlates with aggregation and insolubility. J Biol Chem 288:6130–6139PubMedCentralPubMedGoogle Scholar
  105. 105.
    Fredrickson EK, Rosenbaum JC, Locke MN, Milac TI, Gardner RG (2011) Exposed hydrophobicity is a key determinant of nuclear quality control degradation. Mol Biol Cell 22:2384–2395PubMedCentralPubMedGoogle Scholar
  106. 106.
    Fredrickson EK, Clowes Candadai SV, Tam CH, Gardner RG (2013) Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction. Mol Biol Cell 24:1041–1052PubMedCentralPubMedGoogle Scholar
  107. 107.
    Matsuo Y, Kishimoto H, Tanae K, Kitamura K, Katayama S, Kawamukai M (2011) Nuclear protein quality is regulated by the ubiquitin-proteasome system through the activity of Ubc4 and San1 in fission yeast. J Biol Chem 286:13775–13790Google Scholar
  108. 108.
    Iwata A, Nagashima Y, Matsumoto L, Suzuki T, Yamanaka T, Date H, Deoka K, Nukina N, Tsuji S (2009) Intra-nuclear degradation of polyglutamine aggregates by the ubiquitin proteasome system. J Biol Chem 284:9796–9803PubMedCentralPubMedGoogle Scholar
  109. 109.
    Mishra A, Dikshit P, Purkayastha S, Sharma J, Nukina N, Jana NR (2008) E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity. J Biol Chem 283:7648–7656PubMedGoogle Scholar
  110. 110.
    Tasaki T, Sriram SM, Park KS, Kwon YT (2012) The N-end rule pathway. Annu Rev Biochem 81:261–289PubMedCentralPubMedGoogle Scholar
  111. 111.
    Sultana R, Theodoraki MA, Caplan AJ (2012) UBR1 promotes protein kinase quality control and sensitizes cells to Hsp90 inhibition. Exp Cell Res 318:53–60PubMedCentralPubMedGoogle Scholar
  112. 112.
    Bartel B, Wunning I, Varshavsky A (1990) The recognition component of the N-end rule pathway. EMBO J 9:3179–3189PubMedCentralPubMedGoogle Scholar
  113. 113.
    Xia Z, Webster A, Du F, Piatkov K, Ghislain M, Varshavsky A (2008) Substrate-binding sites of UBR1, the ubiquitin ligase of the N-end rule pathway. J Biol Chem 283:24011–24028PubMedCentralPubMedGoogle Scholar
  114. 114.
    Varshavsky A (2011) The N-end rule pathway and regulation by proteolysis. Protein Sci 20:1298–1345Google Scholar
  115. 115.
    Shemorry A, Hwang CS, Varshavsky A (2013) Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway. Mol Cell 50:540–551PubMedGoogle Scholar
  116. 116.
    Hwang CS, Shemorry A, Varshavsky A (2010) N-terminal acetylation of cellular proteins creates specific degradation signals. Science 327:973–977PubMedGoogle Scholar
  117. 117.
    Piatkov KI, Brower CS, Varshavsky A (2012) The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments. Proc Natl Acad Sci USA 109:E1839–E1847PubMedCentralPubMedGoogle Scholar
  118. 118.
    Piatkov KI, Colnaghi L, Bekes M, Varshavsky A, Huang TT (2012) The auto-generated fragment of the Usp1 deubiquitylase is a physiological substrate of the N-end rule pathway. Mol Cell 48:926–933PubMedCentralPubMedGoogle Scholar
  119. 119.
    Rao H, Uhlmann F, Nasmyth K, Varshavsky A (2001) Degradation of a cohesin subunit by the N-end rule pathway is essential for chromosome stability. Nature 410:955–959PubMedGoogle Scholar
  120. 120.
    Brower CS, Piatkov KI, Varshavsky A (2013) Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway. Mol Cell 50:161–171PubMedPubMedCentralGoogle Scholar
  121. 121.
    Eisele F, Wolf DH (2008) Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett 582:4143–4146PubMedGoogle Scholar
  122. 122.
    Kitamura K, Taki M, Tanaka N, Yamashita I (2011) Fission yeast Ubr1 ubiquitin ligase influences the oxidative stress response via degradation of active Pap1 bZIP transcription factor in the nucleus. Mol Microbiol 80:739–755PubMedGoogle Scholar
  123. 123.
    Swanson R, Locher M, Hochstrasser M (2001) A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev 15:2660–2674PubMedCentralPubMedGoogle Scholar
  124. 124.
    Huyer G, Piluek WF, Fansler Z, Kreft SG, Hochstrasser M, Brodsky JL, Michaelis S (2004) Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J Biol Chem 279:38369–38378PubMedGoogle Scholar
  125. 125.
    Carvalho P, Goder V, Rapoport TA (2006) Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126:361–373PubMedGoogle Scholar
  126. 126.
    Ravid T, Kreft SG, Hochstrasser M (2006) Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J 25:533–543PubMedCentralPubMedGoogle Scholar
  127. 127.
    English AR, Voeltz GK (2013) Endoplasmic reticulum structure and interconnections with other organelles. Cold Spring Harb Perspect Biol 5:a013227PubMedGoogle Scholar
  128. 128.
    Deng M, Hochstrasser M (2006) Spatially regulated ubiquitin ligation by an ER/nuclear membrane ligase. Nature 443:827–831PubMedGoogle Scholar
  129. 129.
    Alfassy OS, Cohen I, Reiss Y, Tirosh B, Ravid T (2013) Placing a disrupted degradation motif at the C terminus of proteasome substrates attenuates degradation without impairing ubiquitylation. J Biol Chem 288:12645–12653PubMedGoogle Scholar
  130. 130.
    Furth N, Gertman O, Shiber A, Alfassy OS, Cohen I, Rosenberg MM, Doron NK, Friedler A, Ravid T (2011) Exposure of bipartite hydrophobic signal triggers nuclear quality control of Ndc10 at the endoplasmic reticulum/nuclear envelope. Mol Biol Cell 22:4726–4739PubMedCentralPubMedGoogle Scholar
  131. 131.
    Kreft SG, Wang L, Hochstrasser M (2006) Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J Biol Chem 281:4646–4653PubMedGoogle Scholar
  132. 132.
    Castro PH, Tavares RM, Bejarano ER, Azevedo H (2012) SUMO, a heavyweight player in plant abiotic stress responses. Cell Mol Life Sci 69:3269–3283PubMedGoogle Scholar
  133. 133.
    Tempe D, Piechaczyk M, Bossis G (2008) SUMO under stress. Biochem Soc Trans 36:874–878PubMedGoogle Scholar
  134. 134.
    Miller MJ, Scalf M, Rytz TC, Hubler SL, Smith LM, Vierstra RD (2013) Quantitative proteomics reveals factors regulating RNA biology as dynamic targets of stress-induced SUMOylation in Arabidopsis. Mol Cell Proteomics 12:449–463PubMedCentralPubMedGoogle Scholar
  135. 135.
    Miller MJ, Barrett-Wilt GA, Hua Z, Vierstra RD (2010) Proteomic analyses identify a diverse array of nuclear processes affected by small ubiquitin-like modifier conjugation in Arabidopsis. Proc Natl Acad Sci USA 107:16512–16517PubMedCentralPubMedGoogle Scholar
  136. 136.
    Golebiowski F, Matic I, Tatham MH, Cole C, Yin Y, Nakamura A, Cox J, Barton GJ, Mann M, Hay RT (2009) System-wide changes to SUMO modifications in response to heat shock. Sci Signal 2: ra24Google Scholar
  137. 137.
    Zhou W, Ryan JJ, Zhou H (2004) Global analyses of sumoylated proteins in Saccharomyces cerevisiae. Induction of protein sumoylation by cellular stresses. J Biol Chem 279:32262–32268PubMedCentralPubMedGoogle Scholar
  138. 138.
    Uzunova K, Gottsche K, Miteva M, Weisshaar SR, Glanemann C, Schnellhardt M, Niessen M, Scheel H, Hofmann K, Johnson ES, Praefcke GJ, Dohmen RJ (2007) Ubiquitin-dependent proteolytic control of SUMO conjugates. J Biol Chem 282:34167–34175PubMedGoogle Scholar
  139. 139.
    Tatham MH, Matic I, Mann M, Hay RT (2011) Comparative proteomic analysis identifies a role for SUMO in protein quality control. Sci Signal 4: rs4Google Scholar
  140. 140.
    Marblestone JG, Edavettal SC, Lim Y, Lim P, Zuo X, Butt TR (2006) Comparison of SUMO fusion technology with traditional gene fusion systems: enhanced expression and solubility with SUMO. Protein Sci 15:182–189PubMedCentralPubMedGoogle Scholar
  141. 141.
    Malakhov MP, Mattern MR, Malakhova OA, Drinker M, Weeks SD, Butt TR (2004) SUMO fusions and SUMO-specific protease for efficient expression and purification of proteins. J Struct Funct Genomics 5:75–86PubMedGoogle Scholar
  142. 142.
    Krumova P, Weishaupt JH (2013) Sumoylation in neurodegenerative diseases. Cell Mol Life Sci 70:2123–2138PubMedGoogle Scholar
  143. 143.
    Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9:13–24PubMedGoogle Scholar
  144. 144.
    Krumova P, Meulmeester E, Garrido M, Tirard M, Hsiao HH, Bossis G, Urlaub H, Zweckstetter M, Kugler S, Melchior F, Bahr M, Weishaupt JH (2011) Sumoylation inhibits alpha-synuclein aggregation and toxicity. J Cell Biol 194:49–60PubMedCentralPubMedGoogle Scholar
  145. 145.
    Ryu J, Cho S, Park BC, Lee do H (2010) Oxidative stress-enhanced SUMOylation and aggregation of ataxin-1: implication of JNK pathway. Biochem Biophys Res Commun 393:280–285PubMedGoogle Scholar
  146. 146.
    Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, Illes K, Lukacsovich T, Zhu YZ, Cattaneo E, Pandolfi PP, Thompson LM, Marsh JL (2004) SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304:100–104PubMedGoogle Scholar
  147. 147.
    Mittler R, Finka A, Goloubinoff P (2012) How do plants feel the heat? Trends Biochem Sci 37:118–125PubMedGoogle Scholar
  148. 148.
    Morano KA, Grant CM, Moye-Rowley WS (2012) The response to heat shock and oxidative stress in Saccharomyces cerevisiae. Genetics 190:1157–1195PubMedCentralPubMedGoogle Scholar
  149. 149.
    Morimoto RI (2011) The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 76:91–99PubMedGoogle Scholar
  150. 150.
    Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899PubMedGoogle Scholar
  151. 151.
    Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298PubMedGoogle Scholar
  152. 152.
    Escusa-Toret S, Vonk WI, Frydman J (2013) Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress. Nat Cell Biol 15:1231–1243PubMedGoogle Scholar
  153. 153.
    Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454:1088–1095PubMedCentralPubMedGoogle Scholar
  154. 154.
    Malinovska L, Kroschwald S, Munder MC, Richter D, Alberti S (2012) Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates. Mol Biol Cell 23:3041–3056PubMedCentralPubMedGoogle Scholar
  155. 155.
    Spokoini R, Moldavski O, Nahmias Y, England JL, Schuldiner M, Kaganovich D (2012) Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast. Cell Rep 2:738–747PubMedGoogle Scholar
  156. 156.
    Tyedmers J, Treusch S, Dong J, McCaffery JM, Bevis B, Lindquist S (2010) Prion induction involves an ancient system for the sequestration of aggregated proteins and heritable changes in prion fragmentation. Proc Natl Acad Sci USA 107:8633–8638PubMedCentralPubMedGoogle Scholar
  157. 157.
    Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898PubMedCentralPubMedGoogle Scholar
  158. 158.
    Weisberg SJ, Lyakhovetsky R, Werdiger AC, Gitler AD, Soen Y, Kaganovich D (2012) Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity. Proc Natl Acad Sci USA 109:15811–15816PubMedCentralPubMedGoogle Scholar
  159. 159.
    Zhang X, Qian SB (2011) Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes. Mol Biol Cell 22:3277–3288PubMedCentralPubMedGoogle Scholar
  160. 160.
    Zaarur N, Meriin AB, Gabai VL, Sherman MY (2008) Triggering aggresome formation. Dissecting aggresome-targeting and aggregation signals in synphilin 1. J Biol Chem 283:27575–27584PubMedGoogle Scholar
  161. 161.
    Garcia-Mata R, Bebok Z, Sorscher EJ, Sztul ES (1999) Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera. J Cell Biol 146:1239–1254PubMedCentralPubMedGoogle Scholar
  162. 162.
    Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, DeMartino GN, Thomas PJ (1999) Dynamic association of proteasomal machinery with the centrosome. J Cell Biol 145:481–490PubMedGoogle Scholar
  163. 163.
    Latonen L, Moore HM, Bai B, Jaamaa S, Laiho M (2011) Proteasome inhibitors induce nucleolar aggregation of proteasome target proteins and polyadenylated RNA by altering ubiquitin availability. Oncogene 30:790–805PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Pamela S. Gallagher
    • 1
  • Michelle L. Oeser
    • 1
    • 2
  • Ayelet-chen Abraham
    • 3
  • Daniel Kaganovich
    • 3
  • Richard G. Gardner
    • 1
    • 2
  1. 1.Department of PharmacologyUniversity of WashingtonSeattleUSA
  2. 2.Molecular and Cellular Biology ProgramUniversity of WashingtonSeattleUSA
  3. 3.Department of Cell and Developmental Biology, Alexander Silberman Institute of Life SciencesHebrew University of JerusalemJerusalemIsrael

Personalised recommendations