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Gene Review

UBI4  -  ubiquitin

Saccharomyces cerevisiae S288c

Synonyms: SCD2, UB14
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Disease relevance of UBI4


Psychiatry related information on UBI4

  • In addition, a set of host genes involved in ubiquitin-dependent protein catabolism affected both TBSV replication and the cytotoxicity of a mutant huntingtin protein, a candidate agent in Huntington's disease [6].

High impact information on UBI4

  • The simultaneous and reinforcing interactions of ESCRT-II GLUE domain with membranes, ESCRT-I, and ubiquitin are critical for ubiquitinated cargo progression from early to late endosomes [7].
  • Fus3 but not Kss1 induces Tec1 ubiquination and degradation through the SCFCdc4 ubiquitin ligase [8].
  • In contrast, we found that the formation of a ubiquitin thiol ester regulates the Cdc34/SCF(Cdc4) binding equilibrium by increasing the dissociation rate constant, with only a minor effect on the association rate [9].
  • By using a F72VCdc34 mutant with increased affinity for the RING domain, we demonstrate that release of ubiquitin-charged Cdc34-S - Ub from the RING is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1 [9].
  • Mechanism of ubiquitin recognition by the CUE domain of Vps9p [10].

Chemical compound and disease context of UBI4

  • Ubiquitin overexpression rescued cells from additional translational inhibitors such as anisomycin and hygromycin B, suggesting that ubiquitin depletion may constitute a widespread mechanism for the toxicity of translational inhibitors [4].
  • hNedd4 and Rsp5p are orthologous ubiquitin ligases that contain a catalytic Hect domain, a C2 domain and multiple WW domains that mediate interactions with proteins. hNedd4 associates with the epithelial sodium channel and mutations disrupting this interaction lead to Liddle's syndrome, a heritable hypertension [11].
  • We propose that heat stress increases phytosphingosine and activates ubiquitin-dependent proteolysis [12].
  • The cellular response to heat stress includes the induction of a group of proteins called the Heat Shock Proteins, whose functions include the synthesis of the thermoprotectant trehalose, refolding of denatured proteins, and ubiquitin- and proteasome-dependent degradation [13].
  • Using yeast cells, we searched for the genes involved in the expression of methylmercury toxicity, and found that genes encoding L-glutamine.D-fructose-6-phosphate amidotransferase (GFAT) and ubiquitin transferase (Ubc3) confer methylmercury resistance on the cells [14].

Biological context of UBI4

  • However, although ubi4/UBI4 diploids can form four initially viable spores, the two ubi4 spores within the ascus lose viability extremely rapidly, apparently a novel phenotype in yeast [1].
  • Sequence analysis revealed that gene PSO4 consists of 1512 bp located upstream of UBI4 on chromosome XII and encodes a putative protein of 56.7 kDa [15].
  • Deletion and promoter fusion studies of the 5' regulatory sequences indicated that two different elements, heat shock elements (HSEs) and stress response element (STREs), contributed independently to heat shock regulation of the UBI4 gene [16].
  • Induction of a hybrid UBI4 5'-CLN3 message in a cdc33-1 mutant previously arrested in G1 also caused entry into a new cell cycle [17].
  • Deletion of UBI4 partially suppressed the growth defects of ump1 mutants, indicating that accumulation of polyubiquitylated proteins is deleterious to cell growth [18].

Anatomical context of UBI4


Associations of UBI4 with chemical compounds

  • After a shift to growth on glucose to repress synthesis of clathrin heavy chains, UBI4 mRNA levels were elevated > 10-fold, whereas the quantity of free ubiquitin declined severalfold relative to that of Chc+ cells [23].
  • Cycloheximide also induces UBI4, the polyubiquitin gene [4].
  • Furthermore, expression of Ub carrying a K-63 to arginine 63 substitution in a strain of Saccharomyces cerevisiae that is missing the poly-Ub gene, UBI4, fails to compensate for the stress defects associated with these cells [24].
  • UBI1-UBI3 expression was repressed in the mutant under 100% O2, while expression of UBI4 was strongly induced [25].
  • UBI4, the polyubiquitin gene of Saccharomyces cerevisiae, is expressed at a low level in vegetative cells, yet induced strongly in response to starvation, cadmium, DNA-damaging agents and heat shock [26].

Physical interactions of UBI4

  • Consistent with this prediction, we have shown by chemical cross-linking the existence of a specific noncovalent Ub binding site on CDC34 [27].
  • However, studies on RPN10-deleted mutants in yeasts have suggested the presence of other multiubiquitin chain-binding factors functioning in ubiquitin-dependent proteolysis [28].
  • Mutagenesis of the perfect consensus for HAP2/3/4 complex binding at position -542 resulted in considerable reduction of UBI4 promoter derepression with respiratory adaptation in HAP wild-type cells and abolished the reduced UBI4-LacZ derepression normally seen when aerobic cultures of the hap1 mutant are transferred from glucose to lactate [29].
  • One of these patches corresponds to a binding site for both HECT and RING domain proteins, suggesting that a single substitution in the catalytic domain of RAD6 confers upon it the ability to interact with multiple ubiquitin protein ligases (E3s) [30].
  • Rad23 contains a ubiquitin-like domain (UbL(R23)) that interacts with catalytically active proteasomes and two ubiquitin (Ub)-associated (UBA) sequences that bind Ub [31].

Enzymatic interactions of UBI4

  • RAD6 and E2(20k) exhibit marked specificity for the conjugation of core histones and catalyze the processive ligation of up to three ubiquitin moieties directly to such model substrates [32].
  • The Ubc3 (Cdc34) enzyme has previously been shown to catalyze the attachment of multiple ubiquitin molecules to model substrates, suggesting that the role of this enzyme in cell cycle progression depends on its targeting an endogenous protein(s) for degradation [33].
  • With the exception of polyubiquitin, the UBP1 protease cleaves at the carboxyl terminus of the ubiquitin moiety in natural and engineered fusions irrespective of their size or the presence of an amino-terminal ubiquitin extension [34].
  • Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway [35].
  • Swe1 is recruited to the neck and hyperphosphorylated before ubiquitin-mediated degradation [36].

Regulatory relationships of UBI4

  • Ub overexpression was found to suppress two other structurally unrelated cdc34 mutations, in addition to the cdc34-2 allele [27].
  • Our results reveal a novel role of ubiquitin in the control of Gap1 trafficking, i.e. direct sorting from the late secretory pathway to the vacuole [19].
  • Northern analysis demonstrated that cells containing either a temperature-sensitive HSF or non-functional Msn2p/Msn4p transcription factors induced high levels of UBI4 transcripts after heat shock [16].
  • Hybrid genes were constructed containing the SUC2 coding region under the control of UBI3 or UBI4 promoters in the yeast vector pLC7 [37].
  • Thus Met4p appears to control its own degradation by regulating the amount of assembled SCF(Met30) ubiquitin ligase [38].

Other interactions of UBI4


Analytical, diagnostic and therapeutic context of UBI4


  1. The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation, and other stresses. Finley, D., Ozkaynak, E., Varshavsky, A. Cell (1987) [Pubmed]
  2. Ubiquitin-specific proteases of Saccharomyces cerevisiae. Cloning of UBP2 and UBP3, and functional analysis of the UBP gene family. Baker, R.T., Tobias, J.W., Varshavsky, A. J. Biol. Chem. (1992) [Pubmed]
  3. Depletion of polyubiquitin encoded by the UBI4 gene confers pleiotropic phenotype to Candida albicans cells. Roig, P., Gozalbo, D. Fungal Genet. Biol. (2003) [Pubmed]
  4. Ubiquitin depletion as a key mediator of toxicity by translational inhibitors. Hanna, J., Leggett, D.S., Finley, D. Mol. Cell. Biol. (2003) [Pubmed]
  5. Production of chemokines CTAPIII and NAP/2 by digestion of recombinant ubiquitin-CTAPIII with yeast ubiquitin C-terminal hydrolase and human immunodeficiency virus protease. Mildner, A.M., Paddock, D.J., LeCureux, L.W., Leone, J.W., Anderson, D.C., Tomasselli, A.G., Heinrikson, R.L. Protein Expr. Purif. (1999) [Pubmed]
  6. Yeast genome-wide screen reveals dissimilar sets of host genes affecting replication of RNA viruses. Panavas, T., Serviene, E., Brasher, J., Nagy, P.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  7. ESCRT-I Core and ESCRT-II GLUE domain structures reveal role for GLUE in linking to ESCRT-I and membranes. Teo, H., Gill, D.J., Sun, J., Perisic, O., Veprintsev, D.B., Vallis, Y., Emr, S.D., Williams, R.L. Cell (2006) [Pubmed]
  8. Fus3-regulated Tec1 degradation through SCFCdc4 determines MAPK signaling specificity during mating in yeast. Chou, S., Huang, L., Liu, H. Cell (2004) [Pubmed]
  9. Release of ubiquitin-charged Cdc34-S - Ub from the RING domain is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1. Deffenbaugh, A.E., Scaglione, K.M., Zhang, L., Moore, J.M., Buranda, T., Sklar, L.A., Skowyra, D. Cell (2003) [Pubmed]
  10. Mechanism of ubiquitin recognition by the CUE domain of Vps9p. Prag, G., Misra, S., Jones, E.A., Ghirlando, R., Davies, B.A., Horazdovsky, B.F., Hurley, J.H. Cell (2003) [Pubmed]
  11. Functional analysis of the human orthologue of the RSP5-encoded ubiquitin protein ligase, hNedd4, in yeast. Gajewska, B., Shcherbik, N., Oficjalska, D., Haines, D.S., Zoładek, T. Curr. Genet. (2003) [Pubmed]
  12. Sphingolipids signal heat stress-induced ubiquitin-dependent proteolysis. Chung, N., Jenkins, G., Hannun, Y.A., Heitman, J., Obeid, L.M. J. Biol. Chem. (2000) [Pubmed]
  13. Why do cells require heat shock proteins to survive heat stress? Riezman, H. Cell Cycle (2004) [Pubmed]
  14. Investigation of intracellular factors involved in methylmercury toxicity. Naganuma, A., Furuchi, T., Miura, N., Hwang, G.W., Kuge, S. Tohoku J. Exp. Med. (2002) [Pubmed]
  15. Allelism of PSO4 and PRP19 links pre-mRNA processing with recombination and error-prone DNA repair in Saccharomyces cerevisiae. Grey, M., Düsterhöft, A., Henriques, J.A., Brendel, M. Nucleic Acids Res. (1996) [Pubmed]
  16. Multiple independent regulatory pathways control UBI4 expression after heat shock in Saccharomyces cerevisiae. Simon, J.R., Treger, J.M., McEntee, K. Mol. Microbiol. (1999) [Pubmed]
  17. CLN3 expression is sufficient to restore G1-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E. Danaie, P., Altmann, M., Hall, M.N., Trachsel, H., Helliwell, S.B. Biochem. J. (1999) [Pubmed]
  18. Regulatory mechanisms controlling biogenesis of ubiquitin and the proteasome. London, M.K., Keck, B.I., Ramos, P.C., Dohmen, R.J. FEBS Lett. (2004) [Pubmed]
  19. Ubiquitin is required for sorting to the vacuole of the yeast general amino acid permease, Gap1. Soetens, O., De Craene, J.O., Andre, B. J. Biol. Chem. (2001) [Pubmed]
  20. A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Sommer, T., Jentsch, S. Nature (1993) [Pubmed]
  21. Yeast RAD6 encoded ubiquitin conjugating enzyme mediates protein degradation dependent on the N-end-recognizing E3 enzyme. Sung, P., Berleth, E., Pickart, C., Prakash, S., Prakash, L. EMBO J. (1991) [Pubmed]
  22. The human ubiquitin carrier protein E2(Mr = 17,000) is homologous to the yeast DNA repair gene RAD6. Schneider, R., Eckerskorn, C., Lottspeich, F., Schweiger, M. EMBO J. (1990) [Pubmed]
  23. Suppressors of clathrin deficiency: overexpression of ubiquitin rescues lethal strains of clathrin-deficient Saccharomyces cerevisiae. Nelson, K.K., Lemmon, S.K. Mol. Cell. Biol. (1993) [Pubmed]
  24. Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain. Arnason, T., Ellison, M.J. Mol. Cell. Biol. (1994) [Pubmed]
  25. Transcriptional remodeling and G1 arrest in dioxygen stress in Saccharomyces cerevisiae. Lee, J., Romeo, A., Kosman, D.J. J. Biol. Chem. (1996) [Pubmed]
  26. Polyubiquitin gene expression contributes to oxidative stress resistance in respiratory yeast (Saccharomyces cerevisiae). Cheng, L., Watt, R., Piper, P.W. Mol. Gen. Genet. (1994) [Pubmed]
  27. Increased ubiquitin expression suppresses the cell cycle defect associated with the yeast ubiquitin conjugating enzyme, CDC34 (UBC3). Evidence for a noncovalent interaction between CDC34 and ubiquitin. Prendergast, J.A., Ptak, C., Arnason, T.G., Ellison, M.J. J. Biol. Chem. (1995) [Pubmed]
  28. Ubiquitin-like proteins and Rpn10 play cooperative roles in ubiquitin-dependent proteolysis. Saeki, Y., Saitoh, A., Toh-e, A., Yokosawa, H. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  29. UBI4, the polyubiquitin gene of Saccharomyces cerevisiae, is a heat shock gene that is also subject to catabolite derepression control. Watt, R., Piper, P.W. Mol. Gen. Genet. (1997) [Pubmed]
  30. Creation of a pluripotent ubiquitin-conjugating enzyme. Ptak, C., Gwozd, C., Huzil, J.T., Gwozd, T.J., Garen, G., Ellison, M.J. Mol. Cell. Biol. (2001) [Pubmed]
  31. Rad23 promotes the targeting of proteolytic substrates to the proteasome. Chen, L., Madura, K. Mol. Cell. Biol. (2002) [Pubmed]
  32. Ubiquitin conjugation by the yeast RAD6 and CDC34 gene products. Comparison to their putative rabbit homologs, E2(20K) AND E2(32K). Haas, A.L., Reback, P.B., Chau, V. J. Biol. Chem. (1991) [Pubmed]
  33. The Ubc3 (Cdc34) ubiquitin-conjugating enzyme is ubiquitinated and phosphorylated in vivo. Goebl, M.G., Goetsch, L., Byers, B. Mol. Cell. Biol. (1994) [Pubmed]
  34. Cloning and functional analysis of the ubiquitin-specific protease gene UBP1 of Saccharomyces cerevisiae. Tobias, J.W., Varshavsky, A. J. Biol. Chem. (1991) [Pubmed]
  35. Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway. Willems, A.R., Lanker, S., Patton, E.E., Craig, K.L., Nason, T.F., Mathias, N., Kobayashi, R., Wittenberg, C., Tyers, M. Cell (1996) [Pubmed]
  36. Coupling morphogenesis to mitotic entry. Sakchaisri, K., Asano, S., Yu, L.R., Shulewitz, M.J., Park, C.J., Park, J.E., Cho, Y.W., Veenstra, T.D., Thorner, J., Lee, K.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  37. Candida albicans UBI3 and UBI4 promoter regions confer differential regulation of invertase production to saccharomyces cerevisiae cells in response to stress. Roig, P., Gozalbo, D. Int. Microbiol. (2002) [Pubmed]
  38. Feedback-regulated degradation of the transcriptional activator Met4 is triggered by the SCF(Met30 )complex. Rouillon, A., Barbey, R., Patton, E.E., Tyers, M., Thomas, D. EMBO J. (2000) [Pubmed]
  39. Intragenic suppression among CDC34 (UBC3) mutations defines a class of ubiquitin-conjugating catalytic domains. Liu, Y., Mathias, N., Steussy, C.N., Goebl, M.G. Mol. Cell. Biol. (1995) [Pubmed]
  40. Bul1, a new protein that binds to the Rsp5 ubiquitin ligase in Saccharomyces cerevisiae. Yashiroda, H., Oguchi, T., Yasuda, Y., Toh-E, A., Kikuchi, Y. Mol. Cell. Biol. (1996) [Pubmed]
  41. NH4+-induced down-regulation of the Saccharomyces cerevisiae Gap1p permease involves its ubiquitination with lysine-63-linked chains. Springael, J.Y., Galan, J.M., Haguenauer-Tsapis, R., André, B. J. Cell. Sci. (1999) [Pubmed]
  42. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Spence, J., Sadis, S., Haas, A.L., Finley, D. Mol. Cell. Biol. (1995) [Pubmed]
  43. Molecular cloning, expression and characterization of a ubiquitin conjugation enzyme (E2(17)kB) highly expressed in rat testis. Wing, S.S., Jain, P. Biochem. J. (1995) [Pubmed]
  44. A ubiquitin carrier protein from wheat germ is structurally and functionally similar to the yeast DNA repair enzyme encoded by RAD6. Sullivan, M.L., Vierstra, R.D. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
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