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Gene Review

HSP104  -  chaperone ATPase HSP104

Saccharomyces cerevisiae S288c

Synonyms: Heat shock protein 104, L0948, Protein aggregation-remodeling factor HSP104, YLL026W
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Disease relevance of HSP104

  • The HSP104 gene, which is largely responsible for induced thermotolerance in yeast, was necessary for life extension induced by transient heat stress [1].
  • The thermoprotective effect in anaerobic cells was not due to expression of HSP104 or any other heat shock gene, raising the possibility that the toxicity of lethal heat shock is due mainly to oxidative stress [2].
  • Hsp104 cooperates with the chaperones present in reticulocyte lysates but not with DnaK of E. coli [3].
  • Here we investigate the role of Hsp104 in vivo using a temperature-sensitive Vibrio harveyi luciferase-fusion protein as a test substrate [4].
  • Hsp104 transgenic and control littermates were infected intracerebrally with the ME7 strain of scrapie [5].

Psychiatry related information on HSP104


High impact information on HSP104

  • In Saccharomyces cerevisiae, heat-shock protein hsp104 is vital for tolerance to heat, ethanol and other stresses [7].
  • Mutagenesis of two putative nucleotide-binding sites in hsp104 indicates that both are essential for function in thermotolerance [7].
  • Furthermore, RNA in situ hybridization analysis demonstrates that loss of Hmt1 results in slowed release of HSP104 mRNA from the sites of transcription [8].
  • Sequence analysis of a 102-kD protein, identified previously as a specific Omega RNA-binding protein, revealed homology to the HSP101/HSP104/ClpB family of heat shock proteins and its expression in yeast complemented a thermotolerance defect caused by a deletion of the HSP104 gene [9].
  • A protein-remodeling factor, Hsp104, controls the inheritance of several yeast prions, including those formed by Sup35 and Ure2 [10].

Chemical compound and disease context of HSP104

  • Deletion of the TPS1 gene, encoding the first enzyme in the biosynthesis of trehalose, or the heat shock protein gene HSP104 only resulted in a minor effect on heat stress resistance compared with deletion of these genes in a wild-type background [11].
  • Small Hsps partially suppress toxicity, even in the absence of Hsp104, potentially by sequestering polyglutamine from toxic interactions with other proteins [12].
  • Strikingly, deletion of Hsp104 increases the size of inclusions formed by expanded poly(Q) lacking the proline-rich region and abolishes toxicity [13].

Biological context of HSP104


Anatomical context of HSP104

  • The results obtained clearly indicate that a mild heat shock elicits a hyperpolarization of the inner mitochondrial membrane and such an event is one of several signals triggering the chain of reactions that activates the expression of the HSP104 gene and probably the expression of other heat shock-regulated genes in S. cerevisiae [17].
  • When expressed in the cytosol, Hsp78 can substitute for the homologous heat shock protein Hsp104 in mediating cellular thermotolerance, suggesting a conserved mode of action of the two proteins [18].
  • It has been speculated that trehalose protects proteins and membranes under environmental stress conditions, but recently it was shown to assist the Hsp104 chaperone in refolding of heat-damaged proteins in the yeast cytosol [19].
  • With several independent clone cells of transformants, the levels of luciferase activity and some hsps, such as hsp104, hsp90, hsp70 and hsp26, were examined [20].
  • The cytoplasmic chaperone hsp104 is required for conformational repair of heat-denatured proteins in the yeast endoplasmic reticulum [21].

Associations of HSP104 with chemical compounds


Physical interactions of HSP104

  • Indeed, we find that a pool of heat shock HSP104 transcripts are 3'-end truncated in THO complex mutant as well as sub2 mutant backgrounds [27].
  • Binding to these promoters is rapidly induced by heat stress at 39 degrees . HSF binds to ScSSA1 and HSP104 promoters under non-stress conditions, but at a low level [28].
  • Hsp104 interacts with Hsp90 cochaperones in respiring yeast [29].
  • Hsp104 binds to yeast Sup35 prion fiber but needs other factor(s) to sever it [30].

Enzymatic interactions of HSP104

  • We propose that Hsp104p plays a role in establishing stable [psi+] inheritance by splitting up Sup35p aggregates and thus ensuring equidistribution of the prion-like Sup35p isoform to daughter cells at cell divisions [31].

Regulatory relationships of HSP104

  • Overproduction of the unrelated chaperone protein Hsp82 (Hsp90) neither cured [PSI] nor antagonized the [PSI]-curing effect of overproduced Hsp104 [32].
  • HSF and Msn2/4p can exclusively or cooperatively activate the yeast HSP104 gene [33].
  • We show that Hsp104p greatly stimulates the assembly of Sup35p into fibrils, whereas Ydj1p has inhibitory effect [34].
  • Overproduction of Hsp104p suppressed the accelerated aging of cells lacking Sir2p, and drugs inhibiting damage segregation further demonstrated that spatial quality control is required to rejuvenate the progeny [35].

Other interactions of HSP104

  • Consistent with a role of STREs in the induction of stress resistance, a number of other stress protein genes (e.g. HSP104) are regulated like CTT1 [36].
  • Heat-induced activation of the HSP26, HSP104, and SSA4 genes was attenuated in the mutant, indicating dependence on TFIIE for maximal rates of de novo synthesis [37].
  • Gene disruptions showed that tps2 and hsp104 null mutants each produced moderate heat shock sensitivity in stationary phase cells [26].
  • The results indicate that during the first hours of microvinification there is an increase in the GPDI mRNA levels with a maximum about one hour after inoculation, and a decrease in the amount of HSP12 and HSP104 mRNAs, although with differences between them [38].
  • These results indicate that, in addition to trehalose, Hsp104 and the Msn2/4-controlled genes, other factors exist in S. cerevisiae that can, significantly and independently of the known factors, enhance general stress resistance [11].

Analytical, diagnostic and therapeutic context of HSP104


  1. Heat stress-induced life span extension in yeast. Shama, S., Lai, C.Y., Antoniazzi, J.M., Jiang, J.C., Jazwinski, S.M. Exp. Cell Res. (1998) [Pubmed]
  2. Cytotoxic and genotoxic consequences of heat stress are dependent on the presence of oxygen in Saccharomyces cerevisiae. Davidson, J.F., Schiestl, R.H. J. Bacteriol. (2001) [Pubmed]
  3. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Glover, J.R., Lindquist, S. Cell (1998) [Pubmed]
  4. Protein disaggregation mediated by heat-shock protein Hsp104. Parsell, D.A., Kowal, A.S., Singer, M.A., Lindquist, S. Nature (1994) [Pubmed]
  5. Infection by ME7 prion is not modified in transgenic mice expressing the yeast chaperone Hsp104 in neurons. Dandoy-Dron, F., Bogdanova, A., Beringue, V., Bailly, Y., Tovey, M.G., Laude, H., Dron, M. Neurosci. Lett. (2006) [Pubmed]
  6. Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease. Vacher, C., Garcia-Oroz, L., Rubinsztein, D.C. Hum. Mol. Genet. (2005) [Pubmed]
  7. Hsp104 is a highly conserved protein with two essential nucleotide-binding sites. Parsell, D.A., Sanchez, Y., Stitzel, J.D., Lindquist, S. Nature (1991) [Pubmed]
  8. Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors. Yu, M.C., Bachand, F., McBride, A.E., Komili, S., Casolari, J.M., Silver, P.A. Genes Dev. (2004) [Pubmed]
  9. HSP101 functions as a specific translational regulatory protein whose activity is regulated by nutrient status. Wells, D.R., Tanguay, R.L., Le, H., Gallie, D.R. Genes Dev. (1998) [Pubmed]
  10. Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities. Shorter, J., Lindquist, S. Mol. Cell (2006) [Pubmed]
  11. The high general stress resistance of the Saccharomyces cerevisiae fil1 adenylate cyclase mutant (Cyr1Lys1682) is only partially dependent on trehalose, Hsp104 and overexpression of Msn2/4-regulated genes. Versele, M., Thevelein, J.M., Van Dijck, P. Yeast (2004) [Pubmed]
  12. A chaperone pathway in protein disaggregation. Hsp26 alters the nature of protein aggregates to facilitate reactivation by Hsp104. Cashikar, A.G., Duennwald, M., Lindquist, S.L. J. Biol. Chem. (2005) [Pubmed]
  13. Critical Role of the Proline-rich Region in Huntingtin for Aggregation and Cytotoxicity in Yeast. Dehay, B., Bertolotti, A. J. Biol. Chem. (2006) [Pubmed]
  14. Increased expression of Hsp40 chaperones, transcriptional factors, and ribosomal protein Rpp0 can cure yeast prions. Kryndushkin, D.S., Smirnov, V.N., Ter-Avanesyan, M.D., Kushnirov, V.V. J. Biol. Chem. (2002) [Pubmed]
  15. Gts1p activates SNF1-dependent derepression of HSP104 and TPS1 in the stationary phase of yeast growth. Yaguchi, S., Tsurugi, K. J. Biol. Chem. (2003) [Pubmed]
  16. Upregulation of the Hsp104 chaperone at physiological temperature during recovery from thermal insult. Seppä, L., Hänninen, A.L., Makarow, M. Mol. Microbiol. (2004) [Pubmed]
  17. Do mitochondria regulate the heat-shock response in Saccharomyces cerevisiae? Rikhvanov, E.G., Varakina, N.N., Rusaleva, T.M., Rachenko, E.I., Knorre, D.A., Voinikov, V.K. Curr. Genet. (2005) [Pubmed]
  18. The molecular chaperone Hsp78 confers compartment-specific thermotolerance to mitochondria. Schmitt, M., Neupert, W., Langer, T. J. Cell Biol. (1996) [Pubmed]
  19. Trehalose is required for conformational repair of heat-denatured proteins in the yeast endoplasmic reticulum but not for maintenance of membrane traffic functions after severe heat stress. Simola, M., Hänninen, A.L., Stranius, S.M., Makarow, M. Mol. Microbiol. (2000) [Pubmed]
  20. Role of Hsp70 subfamily, Ssa, in protein folding in yeast cells, seen in luciferase-transformed ssa mutants. Unno, K., Kishido, T., Hosaka, M., Okada, S. Biol. Pharm. Bull. (1997) [Pubmed]
  21. The cytoplasmic chaperone hsp104 is required for conformational repair of heat-denatured proteins in the yeast endoplasmic reticulum. Hänninen, A.L., Simola, M., Saris, N., Makarow, M. Mol. Biol. Cell (1999) [Pubmed]
  22. Yeast adapt to near-freezing temperatures by STRE/Msn2,4-dependent induction of trehalose synthesis and certain molecular chaperones. Kandror, O., Bretschneider, N., Kreydin, E., Cavalieri, D., Goldberg, A.L. Mol. Cell (2004) [Pubmed]
  23. Prion-dependent switching between respiratory competence and deficiency in the yeast nam9-1 mutant. Chacinska, A., Boguta, M., Krzewska, J., Rospert, S. Mol. Cell. Biol. (2000) [Pubmed]
  24. Metabolic regulation of the trehalose content of vegetative yeast. Winkler, K., Kienle, I., Burgert, M., Wagner, J.C., Holzer, H. FEBS Lett. (1991) [Pubmed]
  25. Phase-specific gene expression in Saccharomyces cerevisiae, using maltose as carbon source under oxygen-limiting conditions. Donalies, U.E., Stahl, U. Curr. Genet. (2001) [Pubmed]
  26. Synergy between trehalose and Hsp104 for thermotolerance in Saccharomyces cerevisiae. Elliott, B., Haltiwanger, R.S., Futcher, B. Genetics (1996) [Pubmed]
  27. Interactions between mRNA export commitment, 3'-end quality control, and nuclear degradation. Libri, D., Dower, K., Boulay, J., Thomsen, R., Rosbash, M., Jensen, T.H. Mol. Cell. Biol. (2002) [Pubmed]
  28. Effects of heat stress on yeast heat shock factor-promoter binding in vivo. Li, N., Zhang, L.M., Zhang, K.Q., Deng, J.S., Prandl, R., Schoffl, F. Acta Biochim. Biophys. Sin. (Shanghai) (2006) [Pubmed]
  29. Hsp104 interacts with Hsp90 cochaperones in respiring yeast. Abbas-Terki, T., Donzé, O., Briand, P.A., Picard, D. Mol. Cell. Biol. (2001) [Pubmed]
  30. Hsp104 binds to yeast Sup35 prion fiber but needs other factor(s) to sever it. Inoue, Y., Taguchi, H., Kishimoto, A., Yoshida, M. J. Biol. Chem. (2004) [Pubmed]
  31. Propagation of the yeast prion-like [psi+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor. Paushkin, S.V., Kushnirov, V.V., Smirnov, V.N., Ter-Avanesyan, M.D. EMBO J. (1996) [Pubmed]
  32. Antagonistic interactions between yeast chaperones Hsp104 and Hsp70 in prion curing. Newnam, G.P., Wegrzyn, R.D., Lindquist, S.L., Chernoff, Y.O. Mol. Cell. Biol. (1999) [Pubmed]
  33. HSF and Msn2/4p can exclusively or cooperatively activate the yeast HSP104 gene. Grably, M.R., Stanhill, A., Tell, O., Engelberg, D. Mol. Microbiol. (2002) [Pubmed]
  34. Molecular chaperones and the assembly of the prion Sup35p, an in vitro study. Krzewska, J., Melki, R. EMBO J. (2006) [Pubmed]
  35. Accelerated aging and failure to segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p. Erjavec, N., Larsson, L., Grantham, J., Nyström, T. Genes Dev. (2007) [Pubmed]
  36. The HOG pathway controls osmotic regulation of transcription via the stress response element (STRE) of the Saccharomyces cerevisiae CTT1 gene. Schüller, C., Brewster, J.L., Alexander, M.R., Gustin, M.C., Ruis, H. EMBO J. (1994) [Pubmed]
  37. A debilitating mutation in transcription factor IIE with differential effects on gene expression in yeast. Tijerina, P., Sayre, M.H. J. Biol. Chem. (1998) [Pubmed]
  38. Study of the first hours of microvinification by the use of osmotic stress-response genes as probes. Pérez-Torrado, R., Carrasco, P., Aranda, A., Gimeno-Alcañiz, J., Pérez-Ortín, J.E., Matallana, E., del Olmo, M.L. Syst. Appl. Microbiol. (2002) [Pubmed]
  39. Acquisition of tolerance against oxidative damage in Saccharomyces cerevisiae. Pereira, M.D., Eleutherio, E.C., Panek, A.D. BMC Microbiol. (2001) [Pubmed]
  40. Saccharomyces cerevisiae Hsp104 protein. Purification and characterization of ATP-induced structural changes. Parsell, D.A., Kowal, A.S., Lindquist, S. J. Biol. Chem. (1994) [Pubmed]
  41. Direct evidence for the intracellular localization of Hsp104 in Saccharomyces cerevisiae by immunoelectron microscopy. Kawai, R., Fujita, K., Iwahashi, H., Komatsu, Y. Cell Stress Chaperones (1999) [Pubmed]
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