Gene Symbol: DOA4
Description: ubiquitin-specific protease DOA4
Alias: DOS1, MUT4, NPI2, SSV7, UBP4, ubiquitin-specific protease DOA4
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. Papa F, Hochstrasser M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene. Nature. 1993;366:313-9 pubmed
    ..We describe a yeast enzyme, Doa4, that is integral to the degradation of ubiquitinated proteins and is required in diverse physiological processes...
  2. Amerik AYu -, Swaminathan S, Krantz B, Wilkinson K, Hochstrasser M. In vivo disassembly of free polyubiquitin chains by yeast Ubp14 modulates rates of protein degradation by the proteasome. EMBO J. 1997;16:4826-38 pubmed
    ..We propose that Ubp14 and isopeptidase T facilitate proteolysis in vivo by preventing unanchored ubiquitin chains from competitively inhibiting polyubiquitin-substrate binding to the 26S proteasome. ..
  3. Luhtala N, Odorizzi G. Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes. J Cell Biol. 2004;166:717-29 pubmed
    ..We show that the loss of Bro1 function is suppressed by the overexpression of DOA4, which encodes the ubiquitin thiolesterase required for the removal of ubiquitin from MVB cargoes...
  4. Amerik A, Nowak J, Swaminathan S, Hochstrasser M. The Doa4 deubiquitinating enzyme is functionally linked to the vacuolar protein-sorting and endocytic pathways. Mol Biol Cell. 2000;11:3365-80 pubmed
    The Saccharomyces cerevisiae DOA4 gene encodes a deubiquitinating enzyme that is required for rapid degradation of ubiquitin-proteasome pathway substrates...
  5. Dupre S, Haguenauer Tsapis R. Deubiquitination step in the endocytic pathway of yeast plasma membrane proteins: crucial role of Doa4p ubiquitin isopeptidase. Mol Cell Biol. 2001;21:4482-94 pubmed
    ..Compared to pep4 cells, pep4 doa4 cells have huge amounts of membrane-bound ubiquitin conjugates...
  6. Bowers K, Lottridge J, Helliwell S, Goldthwaite L, Luzio J, Stevens T. Protein-protein interactions of ESCRT complexes in the yeast Saccharomyces cerevisiae. Traffic. 2004;5:194-210 pubmed
    ..We propose the formation of a large multimeric complex on the endosome membrane consisting of ESCRTI, ESCRTII, ESCRTIII and other associated proteins. ..
  7. Galan J, Haguenauer Tsapis R. Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO J. 1997;16:5847-54 pubmed
    ..We have thus identified a natural target of Lys63-linked ubiquitin chains. We have also shown that monoubiquitination is sufficient to induce permease endocytosis, but that Lys63-linked ubiquitin chains appear to stimulate this process. ..
  8. Papa F, Amerik A, Hochstrasser M. Interaction of the Doa4 deubiquitinating enzyme with the yeast 26S proteasome. Mol Biol Cell. 1999;10:741-56 pubmed
    e Saccharomyces cerevisiae Doa4 deubiquitinating enzyme is required for the rapid degradation of protein substrates of the ubiquitin-proteasome pathway...
  9. Swaminathan S, Amerik A, Hochstrasser M. The Doa4 deubiquitinating enzyme is required for ubiquitin homeostasis in yeast. Mol Biol Cell. 1999;10:2583-94 pubmed
    ..We identified previously a yeast deubiquitinating enzyme, Doa4, that plays a central role in ubiquitin-dependent proteolysis by the proteasome...

More Information


  1. Losko S, Kopp F, Kranz A, Kölling R. Uptake of the ATP-binding cassette (ABC) transporter Ste6 into the yeast vacuole is blocked in the doa4 Mutant. Mol Biol Cell. 2001;12:1047-59 pubmed
    ..step in the trafficking pathway, we examined the intracellular localization of Ste6 in the ubiquitination-deficient doa4 mutant by immunofluorescence experiments, with a Ste6-green fluorescent protein fusion protein and by sucrose ..
  2. Singer J, Manning B, Formosa T. Coordinating DNA replication to produce one copy of the genome requires genes that act in ubiquitin metabolism. Mol Cell Biol. 1996;16:1356-66 pubmed
    ..The mutation principally responsible for this phenotype is in the DOA4 gene, which encodes a ubiquitin hydrolase, one of several yeast genes that encode enzymes that can remove the ..
  3. Waite A, Shou W. Adaptation to a new environment allows cooperators to purge cheaters stochastically. Proc Natl Acad Sci U S A. 2012;109:19079-86 pubmed publisher
    ..We speculate that adaptation to changing environments may contribute to the persistence of cooperative systems before the appearance of more sophisticated mechanisms of cheater control. ..
  4. London M, Keck B, Ramos P, Dohmen R. Regulatory mechanisms controlling biogenesis of ubiquitin and the proteasome. FEBS Lett. 2004;567:259-64 pubmed
    ..Up-regulation of proteasome genes in response to DNA damage, in contrast, is shown to operate via induction of RPN4 transcription. ..
  5. Galan J, Cantegrit B, Garnier C, Namy O, Haguenauer Tsapis R. 'ER degradation' of a mutant yeast plasma membrane protein by the ubiquitin-proteasome pathway. FASEB J. 1998;12:315-23 pubmed
    ..These findings provide an example of a yeast plasma membrane protein that is routed to the 'ER degradation' pathway, and highlight the versatility of the ubiquitin system. ..
  6. Johnson N, West M, Odorizzi G. Regulation of yeast ESCRT-III membrane scission activity by the Doa4 ubiquitin hydrolase. Mol Biol Cell. 2017;28:661-672 pubmed publisher
    ..that in Saccharomyces cerevisiae, ESCRT-III complexes are stabilized and ILV membrane scission is delayed by Doa4, which is the ubiquitin hydrolase that deubiquitinates transmembrane proteins sorted as cargoes into ILVs...
  7. Wolters N, Amerik A. The N-terminal domains determine cellular localization and functions of the Doa4 and Ubp5 deubiquitinating enzymes. Biochem Biophys Res Commun. 2015;467:570-6 pubmed publisher
    ..Genome of the yeast Saccharomyces cerevisiae encodes structurally related but functionally distinct enzymes - Doa4 and Ubp5...
  8. Richter C, West M, Odorizzi G. Doa4 function in ILV budding is restricted through its interaction with the Vps20 subunit of ESCRT-III. J Cell Sci. 2013;126:1881-90 pubmed publisher
    ..We identified a putative MIT domain at the N-terminus of Doa4, which is the ubiquitin (Ub) hydrolase in Saccharomyces cerevisiae that deubiquitinates ILV cargo proteins...
  9. Lucero P, Lagunas R. Catabolite inactivation of the yeast maltose transporter requires ubiquitin-ligase npi1/rsp5 and ubiquitin-hydrolase npi2/doa4. FEMS Microbiol Lett. 1997;147:273-7 pubmed
    ..Using mutants deficient in npi1/rsp5 ubiquitin-protein ligase and npi2/doa4 ubiquitin-protein hydrolase, we have shown that these two enzymes are required for normal endocytosis and ..
  10. Kimura Y, Yashiroda H, Kudo T, Koitabashi S, Murata S, Kakizuka A, et al. An inhibitor of a deubiquitinating enzyme regulates ubiquitin homeostasis. Cell. 2009;137:549-59 pubmed publisher
    ..Rfu1 functions as an inhibitor of Doa4, a deubiquitinating enzyme...
  11. Cheng H, Bao X, Rao H. The F-box Protein Rcy1 Is Involved in the Degradation of Histone H3 Variant Cse4 and Genome Maintenance. J Biol Chem. 2016;291:10372-7 pubmed publisher
    ..Our results reveal the involvement of Rcy1 in chromosome regulation and another regulatory pathway controlling the Cse4 level and activity. ..
  12. Mullally J, Chernova T, Wilkinson K. Doa1 is a Cdc48 adapter that possesses a novel ubiquitin binding domain. Mol Cell Biol. 2006;26:822-30 pubmed
    ..Combined, our data suggest that Doa1 plays a physiological role as a ubiquitin binding cofactor of Cdc48 and that human PLAA may play an analogous role via its interaction with p97/VCP. ..
  13. Miura T, Abe F. Multiple ubiquitin-specific protease genes are involved in degradation of yeast tryptophan permease Tat2 at high pressure. FEMS Microbiol Lett. 2004;239:171-9 pubmed
    ..Here we show that of 17 ubiquitin-specific protease genes (UBP), deletion of DOA4, UBP6 or UBP14 causes stabilization of Tat2 and hence the cells can grow at 25 MPa...
  14. Amerik A, Sindhi N, Hochstrasser M. A conserved late endosome-targeting signal required for Doa4 deubiquitylating enzyme function. J Cell Biol. 2006;175:825-35 pubmed
    Enzyme specificity in vivo is often controlled by subcellular localization. Yeast Doa4, a deubiquitylating enzyme (DUB), removes ubiquitin from membrane proteins destined for vacuolar degradation...
  15. Peters T, Miller A, Tourette C, Agren H, Hubbard A, Hughes R. Genomic Analysis of ATP Efflux in Saccharomyces cerevisiae. G3 (Bethesda). 2015;6:161-70 pubmed publisher
    ..These results will facilitate analysis of ATP efflux mechanisms in higher eukaryotes. ..
  16. Eguez L, Chung Y, Kuchibhatla A, Paidhungat M, Garrett S. Yeast Mn2+ transporter, Smf1p, is regulated by ubiquitin-dependent vacuolar protein sorting. Genetics. 2004;167:107-17 pubmed
    ..cdc1(Ts) conditional growth is also alleviated by mutations, including doa4 and ubc4, that compromise protein ubiquitination, and these ubiquitination defects are associated with Smf1p ..
  17. Wang S, Thibault G, Ng D. Routing misfolded proteins through the multivesicular body (MVB) pathway protects against proteotoxicity. J Biol Chem. 2011;286:29376-87 pubmed publisher
    ..Eliminating the MVB sorting signal diverted molecules to the vacuolar limiting membrane, resulting in the generation of toxic by-products. These data demonstrate a new role of the MVB pathway in protein quality control. ..
  18. Forsberg H, Hammar M, Andreasson C, Moliner A, Ljungdahl P. Suppressors of ssy1 and ptr3 null mutations define novel amino acid sensor-independent genes in Saccharomyces cerevisiae. Genetics. 2001;158:973-88 pubmed
    ..Several of the class II genes (DOA4, UBA1, BRO1, BUL1, RSP5, VPS20, VPS36) encode proteins implicated in controlling aspects of post-Golgi endosomal-..
  19. Umebayashi K, Nakano A. Ergosterol is required for targeting of tryptophan permease to the yeast plasma membrane. J Cell Biol. 2003;161:1117-31 pubmed
    ..The sorting mechanisms of Tat2p that depend on both sterol and ubiquitin will be discussed. ..
  20. Fiorani P, Reid R, Schepis A, Jacquiau H, Guo H, Thimmaiah P, et al. The deubiquitinating enzyme Doa4p protects cells from DNA topoisomerase I poisons. J Biol Chem. 2004;279:21271-81 pubmed
    ..Mutant alleles of three genes, DOA4, SLA1 and SLA2, were recovered...
  21. Tong Z, Kim M, Pandey A, Espenshade P. Identification of candidate substrates for the Golgi Tul1 E3 ligase using quantitative diGly proteomics in yeast. Mol Cell Proteomics. 2014;13:2871-82 pubmed publisher
    ..This quantitative diGly proteomics methodology will serve as a robust platform for screening for stress conditions that require Tul1 E3 ligase activity. ..
  22. Rothfels K, Tanny J, Molnár E, Friesen H, Commisso C, Segall J. Components of the ESCRT pathway, DFG16, and YGR122w are required for Rim101 to act as a corepressor with Nrg1 at the negative regulatory element of the DIT1 gene of Saccharomyces cerevisiae. Mol Cell Biol. 2005;25:6772-88 pubmed
    ..Interestingly, Rim101 was processed in bro1 and doa4 strains but was unable to mediate efficient repression.
  23. Lucero P, Peñalver E, Vela L, Lagunas R. Monoubiquitination is sufficient to signal internalization of the maltose transporter in Saccharomyces cerevisiae. J Bacteriol. 2000;182:241-3 pubmed
    ..This result shows that binding of ubiquitin-Lys63 chains is not required for maximal internalization of all 12-TMS-containing proteins. ..
  24. Aguilar Henonin L, Bravo J, Guzman P. Genetic interactions of a putative Arabidopsis thaliana ubiquitin-ligase with components of the Saccharomyces cerevisiae ubiquitination machinery. Curr Genet. 2006;50:257-68 pubmed
    ..proposed in which Ubc4 and ATL2 act together to target for degradation one or more essential yeast proteins, Doa4/Ubp4, Ubp6 and Ubp14 have a role in disassembling ubiquitin chains on the target proteins and Ubp15 protects ATL2 from ..
  25. Nikko E, Andre B. Split-ubiquitin two-hybrid assay to analyze protein-protein interactions at the endosome: application to Saccharomyces cerevisiae Bro1 interacting with ESCRT complexes, the Doa4 ubiquitin hydrolase, and the Rsp5 ubiquitin ligase. Eukaryot Cell. 2007;6:1266-77 pubmed
    ..Rather, this PRD interacts with the Doa4 deubiquitinating enzyme to recruit it to the endosome...
  26. Kingsbury J, McCusker J. Homoserine toxicity in Saccharomyces cerevisiae and Candida albicans homoserine kinase (thr1Delta) mutants. Eukaryot Cell. 2010;9:717-28 pubmed publisher
    ..Since the doa4Delta and proteasome mutants identified have reduced ubiquitin- and/or proteasome-mediated proteolysis, the degradation of a particular protein or subset of proteins likely contributes to homoserine toxicity...
  27. Nikko E, Andre B. Evidence for a direct role of the Doa4 deubiquitinating enzyme in protein sorting into the MVB pathway. Traffic. 2007;8:566-81 pubmed
    ..In this process, ubiquitin serves as a sorting signal for most cargoes. The yeast ubiquitin hydrolase Doa4 acts late in the MVB pathway...
  28. Richter C, West M, Odorizzi G. Dual mechanisms specify Doa4-mediated deubiquitination at multivesicular bodies. EMBO J. 2007;26:2454-64 pubmed
    b>Doa4 is a ubiquitin-specific protease in Saccharomyces cerevisiae that deubiquitinates integral membrane proteins sorted into the lumenal vesicles of late-endosomal multivesicular bodies (MVBs)...
  29. Auld K, Hitchcock A, Doherty H, Frietze S, Huang L, Silver P. The conserved ATPase Get3/Arr4 modulates the activity of membrane-associated proteins in Saccharomyces cerevisiae. Genetics. 2006;174:215-27 pubmed
    ..In combination, our characterization of GET3 genetic and biochemical interactions with NPL4, GET1, and GET2 implicates Get3 in multiple membrane-dependent pathways. ..
  30. Chernova T, Allen K, Wesoloski L, Shanks J, Chernoff Y, Wilkinson K. Pleiotropic effects of Ubp6 loss on drug sensitivities and yeast prion are due to depletion of the free ubiquitin pool. J Biol Chem. 2003;278:52102-15 pubmed
    ..These data link the Ub system to prion expression and propagation and have broad implications for other neuronal inclusion body diseases. ..