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Gene Review

RSP5  -  NEDD4 family E3 ubiquitin-protein ligase

Saccharomyces cerevisiae S288c

Synonyms: E3 ubiquitin-protein ligase RSP5, MDP1, MUT2, NPI1, Reverses SPT-phenotype protein 5, ...
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Disease relevance of RSP5

  • Over-expression of RSP5 also mimics the sensitivity of ess1ts mutant cells to the toxicity of plasmids carrying dominant-negative CTD mutations, whereas mutations in RSP5 suppress this effect [1].
  • The rsp5 mutants also showed hypersensitivity to various stresses (toxic amino acid analogues, high temperature in a rich medium, and oxidative treatments) and defects in spore growth [2].
  • Two cellular proteins, NPI-1 and NPI-3, were previously identified through their interaction with the influenza virus nucleoprotein (NP) by using the yeast two-hybrid system [3].
  • The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal [3].
  • 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 [4].

High impact information on RSP5

  • SCF(Met30), SCF(Grr1) and Rsp5 ubiquitin ligases are the key actors of the ubiquitin-dependent remodeling of methionine transport [5].
  • The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme [6].
  • Rup1, a previously uncharacterized UBA domain protein, was required for binding of Rsp5 to Ubp2 both in vitro and in vivo [6].
  • Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins [7].
  • These results demonstrate that the C2 domain specifies Rsp5-dependent ubiquitination of endosomal cargo and suggest that Rsp5 function is regulated by membrane phosphoinositides [8].

Biological context of RSP5

  • Cells harboring only the smm1 mutation themselves display temperature-sensitive growth and aberrant mitochondrial inheritance and morphology at the nonpermissive temperature. smm1 maps to RSP5, a gene encoding an essential ubiquitin-protein ligase [9].
  • By screening through a yeast genomic library, the mutant was found to carry an allele of RSP5 encoding an E3 ubiquitin ligase [2].
  • RSP5 is an essential gene in Saccharomyces cerevisiae and was recently shown to form a physical and functional complex with RNA polymerase II (RNA pol II) [10].
  • Chromosomal deletion of NPl1/RSP5 showed that this gene is essential for cell viability [11].
  • A screen for single-copy suppressors of the cycloheximide sensitivity of tricalbin mutants yielded RSP5, which encodes a C2-domain-containing, ubiquitin-conjugating ligase essential for receptor-mediated and fluid phase endocytosis [12].

Anatomical context of RSP5


Associations of RSP5 with chemical compounds

  • We show here that Rpb1 ubiquitination and degradation are induced in vivo by UV irradiation and by the UV-mimetic compound 4-nitroquinoline-1-oxide (4-NQO) and that a functional RSP5 gene product is required for this effect [17].
  • A promoter mutation that reduces expression of RSP5/NPI1, a postulated ubiquitin-protein ligase, dramatically reduces the rate of glucose-induced proteolysis of maltose permease [18].
  • Mutations at the RSP5 locus alter the glucose-triggered K(m) decrease [19].
  • The ZZZ1 and MDP1/RSP5 gene products appear to play important roles in determining effective anesthetic dose in yeast since increased levels of either gene increases isoflurane sensitivity whereas decreased activity decreases sensitivity [20].
  • The data presented reveal that mdp1 mutants are also pH sensitive, and hypersensitive to hygromycin B and paromomycin [21].

Physical interactions of RSP5


Enzymatic interactions of RSP5

  • Fusion of the Rpb1 carboxyl-terminal domain to another protein also causes that protein to be ubiquitinated by Rsp5 [27].
  • Temperature-sensitive rsp5 mutants were unable to ubiquitinate or to internalize Ste2p at the nonpermissive temperature [28].
  • Pho87 and Pho91 are ubiquitinated in vivo in an Rsp5-dependent manner, and the Pho+ phenotype of the spa1-1 suppressor is dependent upon Pho87 and Pho91 [29].

Co-localisations of RSP5


Regulatory relationships of RSP5


Other interactions of RSP5

  • Yeast glycogen synthase kinase 3 is involved in protein degradation in cooperation with Bul1, Bul2, and Rsp5 [23].
  • Twenty-five mutants defining four complementation groups, mdp1, mdp2, mdp3, and mdp4, were found [32].
  • In a genetic screening for multicopy suppressors of the rsp5 mutation, we identified the WSC2/YNL283c gene [19].
  • (iii) Rsp5p and Sla2p coimmunoprecipitate and partially colocalize to punctate structures in wild-type cells [13].
  • The ubiquitin-permease conjugates that are readily demonstrated in wild type cells were barely detectable in npi1 mutant cells, indicating that uracil permease may be a physiological substrate of the Npi1p ubiquitin ligase [33].

Analytical, diagnostic and therapeutic context of RSP5


  1. Genetic interactions between the ESS1 prolyl-isomerase and the RSP5 ubiquitin ligase reveal opposing effects on RNA polymerase II function. Wu, X., Chang, A., Sudol, M., Hanes, S.D. Curr. Genet. (2001) [Pubmed]
  2. A nonconserved Ala401 in the yeast Rsp5 ubiquitin ligase is involved in degradation of Gap1 permease and stress-induced abnormal proteins. Hoshikawa, C., Shichiri, M., Nakamori, S., Takagi, H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal. Wang, P., Palese, P., O'Neill, R.E. J. Virol. (1997) [Pubmed]
  4. 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]
  5. Substrate-mediated remodeling of methionine transport by multiple ubiquitin-dependent mechanisms in yeast cells. Menant, A., Barbey, R., Thomas, D. EMBO J. (2006) [Pubmed]
  6. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme. Kee, Y., Lyon, N., Huibregtse, J.M. EMBO J. (2005) [Pubmed]
  7. Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins. Hettema, E.H., Valdez-Taubas, J., Pelham, H.R. EMBO J. (2004) [Pubmed]
  8. The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo. Dunn, R., Klos, D.A., Adler, A.S., Hicke, L. J. Cell Biol. (2004) [Pubmed]
  9. A role for ubiquitination in mitochondrial inheritance in Saccharomyces cerevisiae. Fisk, H.A., Yaffe, M.P. J. Cell Biol. (1999) [Pubmed]
  10. Rsp5 WW domains interact directly with the carboxyl-terminal domain of RNA polymerase II. Chang, A., Cheang, S., Espanel, X., Sudol, M. J. Biol. Chem. (2000) [Pubmed]
  11. NPl1, an essential yeast gene involved in induced degradation of Gap1 and Fur4 permeases, encodes the Rsp5 ubiquitin-protein ligase. Hein, C., Springael, J.Y., Volland, C., Haguenauer-Tsapis, R., André, B. Mol. Microbiol. (1995) [Pubmed]
  12. Characterization of the yeast tricalbins: membrane-bound multi-C2-domain proteins that form complexes involved in membrane trafficking. Creutz, C.E., Snyder, S.L., Schulz, T.A. Cell. Mol. Life Sci. (2004) [Pubmed]
  13. Rsp5p, a new link between the actin cytoskeleton and endocytosis in the yeast Saccharomyces cerevisiae. Kamińska, J., Gajewska, B., Hopper, A.K., Zoładek, T. Mol. Cell. Biol. (2002) [Pubmed]
  14. Localization of the Rsp5p ubiquitin-protein ligase at multiple sites within the endocytic pathway. Wang, G., McCaffery, J.M., Wendland, B., Dupré, S., Haguenauer-Tsapis, R., Huibregtse, J.M. Mol. Cell. Biol. (2001) [Pubmed]
  15. A single PXY motif located within the carboxyl terminus of Spt23p and Mga2p mediates a physical and functional interaction with ubiquitin ligase Rsp5p. Shcherbik, N., Kee, Y., Lyon, N., Huibregtse, J.M., Haines, D.S. J. Biol. Chem. (2004) [Pubmed]
  16. Rsp5 ubiquitin ligase affects isoprenoid pathway and cell wall organization in S. cerevisiae. Kamińska, J., Kwapisz, M., Grabińska, K., Orłowski, J., Boguta, M., Palamarczyk, G., Zoładek, T. Acta Biochim. Pol. (2005) [Pubmed]
  17. Rsp5 ubiquitin-protein ligase mediates DNA damage-induced degradation of the large subunit of RNA polymerase II in Saccharomyces cerevisiae. Beaudenon, S.L., Huacani, M.R., Wang, G., McDonnell, D.P., Huibregtse, J.M. Mol. Cell. Biol. (1999) [Pubmed]
  18. The role of ubiquitin conjugation in glucose-induced proteolysis of Saccharomyces maltose permease. Medintz, I., Jiang, H., Michels, C.A. J. Biol. Chem. (1998) [Pubmed]
  19. The cell wall integrity/remodeling MAPK cascade is involved in glucose activation of the yeast plasma membrane H(+)-ATPase. de la Fuente, N., Portillo, F. Biochim. Biophys. Acta (2000) [Pubmed]
  20. Ubiquitin metabolism affects cellular response to volatile anesthetics in yeast. Wolfe, D., Reiner, T., Keeley, J.L., Pizzini, M., Keil, R.L. Mol. Cell. Biol. (1999) [Pubmed]
  21. The growth of mdp1/rsp5 mutants of Saccharomyces cerevisiae is affected by mutations in the ATP-binding domain of the plasma membrane H+ -ATPase. Kamińska, J., Tobiasz, A., Gniewosz, M., Zoładek, T. Gene (2000) [Pubmed]
  22. Rsp5p is required for ER bound Mga2p120 polyubiquitination and release of the processed/tethered transactivator Mga2p90. Shcherbik, N., Zoladek, T., Nickels, J.T., Haines, D.S. Curr. Biol. (2003) [Pubmed]
  23. Yeast glycogen synthase kinase 3 is involved in protein degradation in cooperation with Bul1, Bul2, and Rsp5. Andoh, T., Hirata, Y., Kikuchi, A. Mol. Cell. Biol. (2000) [Pubmed]
  24. The PY-motif of Bul1 protein is essential for growth of Saccharomyces cerevisiae under various stress conditions. Yashiroda, H., Kaida, D., Toh-e, A., Kikuchi, Y. Gene (1998) [Pubmed]
  25. Direct sorting of the yeast uracil permease to the endosomal system is controlled by uracil binding and Rsp5p-dependent ubiquitylation. Blondel, M.O., Morvan, J., Dupré, S., Urban-Grimal, D., Haguenauer-Tsapis, R., Volland, C. Mol. Biol. Cell (2004) [Pubmed]
  26. PY motifs of Rod1 are required for binding to Rsp5 and for drug resistance. Andoh, T., Hirata, Y., Kikuchi, A. FEBS Lett. (2002) [Pubmed]
  27. The large subunit of RNA polymerase II is a substrate of the Rsp5 ubiquitin-protein ligase. Huibregtse, J.M., Yang, J.C., Beaudenon, S.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  28. Domains of the Rsp5 ubiquitin-protein ligase required for receptor-mediated and fluid-phase endocytosis. Dunn, R., Hicke, L. Mol. Biol. Cell (2001) [Pubmed]
  29. The Rsp5 E3 ligase mediates turnover of low affinity phosphate transporters in Saccharomyces cerevisiae. Estrella, L.A., Krishnamurthy, S., Timme, C.R., Hampsey, M. J. Biol. Chem. (2008) [Pubmed]
  30. Pressure-induced differential regulation of the two tryptophan permeases Tat1 and Tat2 by ubiquitin ligase Rsp5 and its binding proteins, Bul1 and Bul2. Abe, F., Iida, H. Mol. Cell. Biol. (2003) [Pubmed]
  31. The mRNA nuclear export factor Hpr1 is regulated by Rsp5-mediated ubiquitylation. Gwizdek, C., Hobeika, M., Kus, B., Ossareh-Nazari, B., Dargemont, C., Rodriguez, M.S. J. Biol. Chem. (2005) [Pubmed]
  32. Mutations altering the mitochondrial-cytoplasmic distribution of Mod5p implicate the actin cytoskeleton and mRNA 3' ends and/or protein synthesis in mitochondrial delivery. Zoladek, T., Vaduva, G., Hunter, L.A., Boguta, M., Go, B.D., Martin, N.C., Hopper, A.K. Mol. Cell. Biol. (1995) [Pubmed]
  33. Ubiquitination mediated by the Npi1p/Rsp5p ubiquitin-protein ligase is required for endocytosis of the yeast uracil permease. Galan, J.M., Moreau, V., Andre, B., Volland, C., Haguenauer-Tsapis, R. J. Biol. Chem. (1996) [Pubmed]
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