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PLOS Genetics  2009 

Disease-Associated Mutant Ubiquitin Causes Proteasomal Impairment and Enhances the Toxicity of Protein Aggregates

DOI: 10.1371/journal.pgen.1000382

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Abstract:

Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of AD, much less is known about the sporadic cases. Aggregates found in both familial and sporadic AD often include proteins other than those typically associated with the disease. One such protein is a mutant form of ubiquitin, UBB+1, a frameshift product generated by molecular misreading of a wild-type ubiquitin gene. UBB+1 has been associated with multiple disorders. UBB+1 cannot function as a ubiquitin molecule, and it is itself a substrate for degradation by the ubiquitin/proteasome system (UPS). Accumulation of UBB+1 impairs the proteasome system and enhances toxic protein aggregation, ultimately resulting in cell death. Here, we describe a novel model system to investigate how UBB+1 impairs UPS function and whether it plays a causal role in protein aggregation. We expressed a protein analogous to UBB+1 in yeast (Ubext) and demonstrated that it caused UPS impairment. Blocking ubiquitination of Ubext or weakening its interactions with other ubiquitin-processing proteins reduced the UPS impairment. Expression of Ubext altered the conjugation of wild-type ubiquitin to a UPS substrate. The expression of Ubext markedly enhanced cellular susceptibility to toxic protein aggregates but, surprisingly, did not induce or alter nontoxic protein aggregates in yeast. Taken together, these results suggest that Ubext interacts with more than one protein to elicit impairment of the UPS and affect protein aggregate toxicity. Furthermore, we suggest a model whereby chronic UPS impairment could inflict deleterious consequences on proper protein aggregate sequestration.

References

[1]  Goedert M, Spillantini MG (2006) A century of Alzheimer's disease. Science 314: 777–781.
[2]  Jentsch S (1992) The ubiquitin-conjugation system. Annu Rev Genet 26: 179–207.
[3]  Johnson ES, Bartel B, Seufert W, Varshavsky A (1992) Ubiquitin as a degradation signal. Embo J 11: 497–505.
[4]  Varshavsky A (1997) The ubiquitin system. Trends Biochem Sci 22: 383–387.
[5]  Schwartz AL, Ciechanover A (1999) The ubiquitin-proteasome pathway and pathogenesis of human diseases. Annu Rev Med 50: 57–74.
[6]  Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenerative disease. Science 296: 1991–1995.
[7]  Alves-Rodrigues A, Gregori L, Figueiredo-Pereira ME (1998) Ubiquitin, cellular inclusions and their role in neurodegeneration. Trends Neurosci 21: 516–520.
[8]  Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, et al. (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25: 302–305.
[9]  Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, et al. (2004) UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol 55: 512–521.
[10]  Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427–446.
[11]  van Leeuwen FW, Hol EM, Fischer DF (2006) Frameshift proteins in Alzheimer's disease and in other conformational disorders: time for the ubiquitin-proteasome system. J Alzheimers Dis 9: 319–325.
[12]  van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, et al. (1998) Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science 279: 242–247.
[13]  van Leeuwen FW, Burbach JP, Hol EM (1998) Mutations in RNA: a first example of molecular misreading in Alzheimer's disease. Trends Neurosci 21: 331–335.
[14]  van Leeuwen FW, Fischer DF, Benne R, Hol EM (2000) Molecular misreading. A new type of transcript mutation in gerontology. Ann N Y Acad Sci 908: 267–281.
[15]  van Den Hurk WH, Willems HJ, Bloemen M, Martens GJ (2001) Novel frameshift mutations near short simple repeats. J Biol Chem 276: 11496–11498.
[16]  Hol EM, van Leeuwen FW, Fischer DF (2005) The proteasome in Alzheimer's disease and Parkinson's disease: lessons from ubiquitin B+1. Trends Mol Med 11: 488–495.
[17]  Fischer DF, De Vos RA, Van Dijk R, De Vrij FM, Proper EA, et al. (2003) Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain. Faseb J 17: 2014–2024.
[18]  De Vrij FM, Sluijs JA, Gregori L, Fischer DF, Hermens WT, et al. (2001) Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death. Faseb J 15: 2680–2688.
[19]  Van Leeuwen FW, Hol EM, Hermanussen RW, Sonnemans MA, Moraal E, et al. (2000) Molecular misreading in non-neuronal cells. Faseb J 14: 1595–1602.
[20]  Lam YA, Pickart CM, Alban A, Landon M, Jamieson C, et al. (2000) Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. Proc Natl Acad Sci U S A 97: 9902–9906.
[21]  van Tijn P, de Vrij FM, Schuurman KG, Dantuma NP, Fischer DF, et al. (2007) Dose-dependent inhibition of proteasome activity by a mutant ubiquitin associated with neurodegenerative disease. J Cell Sci 120: 1615–1623.
[22]  Lindsten K, de Vrij FM, Verhoef LG, Fischer DF, van Leeuwen FW, et al. (2002) Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation. J Cell Biol 157: 417–427.
[23]  Fischer DF, van Dijk R, van Tijn P, Hobo B, Verhage MC, et al. (2008) Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging. In press.
[24]  de Pril R, Fischer DF, Maat-Schieman ML, Hobo B, de Vos RA, et al. (2004) Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases. Hum Mol Genet 13: 1803–1813.
[25]  Ozkaynak E, Finley D, Solomon MJ, Varshavsky A (1987) The yeast ubiquitin genes: a family of natural gene fusions. Embo J 6: 1429–1439.
[26]  Treger JM, Heichman KA, McEntee K (1988) Expression of the yeast UB14 gene increases in response to DNA-damaging agents and in meiosis. Mol Cell Biol 8: 1132–1136.
[27]  Finley D, Ozkaynak E, Varshavsky A (1987) The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation, and other stresses. Cell 48: 1035–1046.
[28]  Heinemeyer W, Gruhler A, Mohrle V, Mahe Y, Wolf DH (1993) PRE2, highly homologous to the human major histocompatibility complex-linked RING10 gene, codes for a yeast proteasome subunit necessary for chrymotryptic activity and degradation of ubiquitinated proteins. J Biol Chem 268: 5115–5120.
[29]  Amerik A, Swaminathan S, Krantz BA, Wilkinson KD, Hochstrasser M (1997) In vivo disassembly of free polyubiquitin chains by yeast Ubp14 modulates rates of protein degradation by the proteasome. Embo J 16: 4826–4838.
[30]  Bachmair A, Finley D, Varshavsky A (1986) In vivo half-life of a protein is a function of its amino-terminal residue. Science 234: 179–186.
[31]  Dohmen RJ, Madura K, Bartel B, Varshavsky A (1991) The N-end rule is mediated by the UBC2(RAD6) ubiquitin-conjugating enzyme. Proc Natl Acad Sci U S A 88: 7351–7355.
[32]  Seufert W, Jentsch S (1990) Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. Embo J 9: 543–550.
[33]  Varshavsky A (1997) The N-end rule pathway of protein degradation. Genes Cells 2: 13–28.
[34]  Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, et al. (1992) Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360: 597–599.
[35]  Pegg AE (1986) Recent advances in the biochemistry of polyamines in eukaryotes. Biochem J 234: 249–262.
[36]  Ghoda L, van Daalen Wetters T, Macrae M, Ascherman D, Coffino P (1989) Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation. Science 243: 1493–1495.
[37]  Hoyt MA, Zhang M, Coffino P (2003) Ubiquitin-independent mechanisms of mouse ornithine decarboxylase degradation are conserved between mammalian and fungal cells. J Biol Chem 278: 12135–12143.
[38]  Zhang M, Pickart CM, Coffino P (2003) Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate. Embo J 22: 1488–1496.
[39]  Miyazaki Y, Matsufuji S, Murakami Y, Hayashi S (1993) Single amino-acid replacement is responsible for the stabilization of ornithine decarboxylase in HMOA cells. Eur J Biochem 214: 837–844.
[40]  Hurley JH, Lee S, Prag G (2006) Ubiquitin-binding domains. Biochem J 399: 361–372.
[41]  Wilkinson KD, Ventii KH, Friedrich KL, Mullally JE (2005) The ubiquitin signal: assembly, recognition and termination. Symposium on ubiquitin and signaling. EMBO Rep 6: 815–820.
[42]  Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. Embo J 19: 94–102.
[43]  Pickart CM, Fushman D (2004) Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8: 610–616.
[44]  Lee DH, Sherman MY, Goldberg AL (1996) Involvement of the molecular chaperone Ydj1 in the ubiquitin-dependent degradation of short-lived and abnormal proteins in Saccharomyces cerevisiae. Mol Cell Biol 16: 4773–4781.
[45]  van Nocker S, Sadis S, Rubin DM, Glickman M, Fu H, et al. (1996) The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover. Mol Cell Biol 16: 6020–6028.
[46]  Hochstrasser M (2006) Lingering mysteries of ubiquitin-chain assembly. Cell 124: 27–34.
[47]  Beal R, Deveraux Q, Xia G, Rechsteiner M, Pickart C (1996) Surface hydrophobic residues of multiubiquitin chains essential for proteolytic targeting. Proc Natl Acad Sci U S A 93: 861–866.
[48]  Sloper-Mould KE, Jemc JC, Pickart CM, Hicke L (2001) Distinct functional surface regions on ubiquitin. J Biol Chem 276: 30483–30489.
[49]  Fowden L, Lewis D, Tristram H (1967) Toxic amino acids: their action as antimetabolites. Adv Enzymol Relat Areas Mol Biol 29: 89–163.
[50]  Duennwald ML, Jagadish S, Giorgini F, Muchowski PJ, Lindquist S (2006) A network of protein interactions determines polyglutamine toxicity. Proc Natl Acad Sci U S A 103: 11051–11056.
[51]  Duennwald ML, Jagadish S, Muchowski PJ, Lindquist S (2006) Flanking sequences profoundly alter polyglutamine toxicity in yeast. Proc Natl Acad Sci U S A 103: 11045–11050.
[52]  Krobitsch S, Lindquist S (2000) Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc Natl Acad Sci U S A 97: 1589–1594.
[53]  Gokhale KC, Newnam GP, Sherman MY, Chernoff YO (2005) Modulation of prion-dependent polyglutamine aggregation and toxicity by chaperone proteins in the yeast model. J Biol Chem 280: 22809–22818.
[54]  True HL, Lindquist SL (2000) A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407: 477–483.
[55]  Tuite MF, Cox BS (2003) Propagation of yeast prions. Nat Rev Mol Cell Biol 4: 878–890.
[56]  Shorter J, Lindquist S (2005) Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6: 435–450.
[57]  Chernoff YO, Uptain SM, Lindquist SL (2002) Analysis of prion factors in yeast. Methods Enzymol 351: 499–538.
[58]  Ter-Avanesyan MD, Kushnirov VV, Dagkesamanskaya AR, Didichenko SA, Chernoff YO, et al. (1993) Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non-overlapping functional regions in the encoded protein. Mol Microbiol 7: 683–692.
[59]  Dagkesamanskaya AR, Ter-Avanesyan MD (1991) Interaction of the yeast omnipotent suppressors SUP1(SUP45) and SUP2(SUP35) with non-mendelian factors. Genetics 128: 513–520.
[60]  Chernoff YO, Inge-Vechtomov SG, Derkach IL, Ptyushkina MV, Tarunina OV, et al. (1992) Dosage-dependent translational suppression in yeast Saccharomyces cerevisiae. Yeast 8: 489–499.
[61]  Chernova TA, Allen KD, Wesoloski LM, Shanks JR, Chernoff YO, et al. (2003) Pleiotropic effects of Ubp6 loss on drug sensitivities and yeast prion are due to depletion of the free ubiquitin pool. J Biol Chem 278: 52102–52115.
[62]  Allen KD, Chernova TA, Tennant EP, Wilkinson KD, Chernoff YO (2007) Effects of ubiquitin system alterations on the formation and loss of a yeast prion. J Biol Chem 282: 3004–3013.
[63]  Tank EM, Harris DA, Desai AA, True HL (2007) Prion protein repeat expansion results in increased aggregation and reveals phenotypic variability. Mol Cell Biol 27: 5445–5455.
[64]  Chernoff YO, Lindquist SL, Ono B, Inge-Vechtomov SG, Liebman SW (1995) Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268: 880–884.
[65]  Derkatch IL, Bradley ME, Liebman SW (1998) Overexpression of the SUP45 gene encoding a Sup35p-binding protein inhibits the induction of the de novo appearance of the [PSI+] prion. Proc Natl Acad Sci U S A 95: 2400–2405.
[66]  Ter-Avanesyan MD, Dagkesamanskaya AR, Kushnirov VV, Smirnov VN (1994) The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae. Genetics 137: 671–676.
[67]  Kryndushkin DS, Alexandrov IM, Ter-Avanesyan MD, Kushnirov VV (2003) Yeast [PSI+] prion aggregates are formed by small Sup35 polymers fragmented by Hsp104. J Biol Chem 278: 49636–49643.
[68]  Bagriantsev SN, Gracheva EO, Richmond JE, Liebman SW (2008) Variant-specific [PSI+] infection is transmitted by Sup35 polymers within [PSI+] aggregates with heterogeneous protein composition. Mol Biol Cell 19: 2433–2443.
[69]  Kaganovich D, Kopito R, Frydman J (2008) Misfolded proteins partition between two distinct quality control compartments. Nature 454: 1088–1095.
[70]  Wang Y, Meriin AB, Zaarur N, Romanova NV, Chernoff YO, et al. (2008) Abnormal proteins can form aggresome in yeast: aggresome-targeting signals and components of the machinery. Faseb J. In press.
[71]  Ghaboosi N, Deshaies RJ (2007) A conditional yeast E1 mutant blocks the ubiquitin-proteasome pathway and reveals a role for ubiquitin conjugates in targeting Rad23 to the proteasome. Mol Biol Cell 18: 1953–1963.
[72]  Lindsten K, Dantuma NP (2003) Monitoring the ubiquitin/proteasome system in conformational diseases. Ageing Res Rev 2: 433–449.
[73]  Ferreira ST, Vieira MN, De Felice FG (2007) Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases. IUBMB Life 59: 332–345.
[74]  Walsh DM, Selkoe DJ (2007) A beta oligomers - a decade of discovery. J Neurochem 101: 1172–1184.
[75]  Guthrie C, Fink G (2004) Guide to Yeast Genetics and Molecular and Cell Biology. San Diego: Elsevier Academic Press.
[76]  Derkatch IL, Chernoff YO, Kushnirov VV, Inge-Vechtomov SG, Liebman SW (1996) Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. Genetics 144: 1375–1386.
[77]  Sambrook J, Russell DW (2001) Molecular cloning : a laboratory manual. Cold Spring Harbor, , N.Y.: Cold Spring Harbor Laboratory Press.
[78]  Mumberg D, Muller R, Funk M (1995) Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds. Gene 156: 119–122.
[79]  Danaie P, Altmann M, Hall MN, Trachsel H, Helliwell SB (1999) CLN3 expression is sufficient to restore G1-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E. Biochem J 340 (Pt 1): 135–141.
[80]  True HL, Berlin I, Lindquist SL (2004) Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431: 184–187.
[81]  Patino MM, Liu JJ, Glover JR, Lindquist S (1996) Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273: 622–626.
[82]  Bagriantsev S, Liebman SW (2004) Specificity of prion assembly in vivo. J Biol Chem 279: 51042–51048.
[83]  Ho AK, Shen TX, Ryan KJ, Kiseleva E, Levy MA, et al. (2000) Assembly and preferential localization of Nup116p on the cytoplasmic face of the nuclear pore complex by interaction with Nup82p. Mol Cell Biol 20: 5736–5748.

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