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Gene Review

DOA4  -  Doa4p

Saccharomyces cerevisiae S288c

Synonyms: D4270, DOS1, Deubiquitinating enzyme 4, MUT4, NPI2, ...
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Disease relevance of DOA4

  • Mutations in DOA4 cause loss of the free ubiquitin pool in cells under heat stress conditions, and extra copies of UB14 restore this pool without restoring coordination of replication [1].

High impact information on DOA4

  • Doa4 appears to function late in the proteolytic pathway by cleaving ubiquitin from substrate remnants still bound to protease [2].
  • Ubiquitin-specific processing protease 5 (Ubp5), the closest paralogue of Doa4, has no functional overlap [3].
  • We show that an N-terminal segment of Doa4 is sufficient for endosome association [3].
  • Overexpression of DOA4 restores cargo protein deubiquitination and sorting via the MVB pathway and reverses the abnormal endosomal morphology typical of bro1 mutant cells, resulting in the restoration of multivesicular endosomes [4].
  • Mutation of Lys 6 in the cytoplasmic tail of Phm5p disrupts its sorting, but sorting is restored, even in doa4 cells, by the biosynthetic addition of a single ubiquitin chain [5].

Biological context of DOA4


Anatomical context of DOA4


Associations of DOA4 with chemical compounds

  • Deletion of DOA4, which causes decreased levels of available ubiquitin, severely decreases the rate of glucose-induced proteolysis, and this is suppressed by the overproduction of ubiquitin [11].
  • To define the ubiquitination-dependent 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 density gradient fractionation [12].

Regulatory relationships of DOA4

  • Together, these data support a model in which Doa4 promotes proteolysis through removal of ubiquitin from proteolytic intermediates on the proteasome before or after initiation of substrate breakdown [13].
  • Uptake of the ATP-binding cassette (ABC) transporter Ste6 into the yeast vacuole is blocked in the doa4 Mutant [12].
  • In turn, Bro1 directly stimulates deubiquitination by interacting with a YPxL motif in the catalytic domain of Doa4 [14].

Other interactions of DOA4

  • Taken together, these findings support a model in which Plc1p mediates an oxidative-stress signal from the plasma membrane that triggers Ume3p destruction through a Doa4p-dependent mechanism [6].
  • Mutant alleles of three genes, DOA4, SLA1 and SLA2, were recovered [15].
  • In contrast, pep4 cells lacking the Doa4p ubiquitin isopeptidase accumulate ubiquitin-conjugated Fur4p [8].
  • These data suggest that Fur4p undergoes Doa4p-dependent deubiquitination prior to vacuolar degradation [8].
  • Additional studies suggest a role for Doa4p in the Rad9p checkpoint response to Top1p poisons [15].


  1. Coordinating DNA replication to produce one copy of the genome requires genes that act in ubiquitin metabolism. Singer, J.D., Manning, B.M., Formosa, T. Mol. Cell. Biol. (1996) [Pubmed]
  2. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene. Papa, F.R., Hochstrasser, M. Nature (1993) [Pubmed]
  3. A conserved late endosome-targeting signal required for Doa4 deubiquitylating enzyme function. Amerik, A., Sindhi, N., Hochstrasser, M. J. Cell Biol. (2006) [Pubmed]
  4. Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes. Luhtala, N., Odorizzi, G. J. Cell Biol. (2004) [Pubmed]
  5. Sorting of proteins into multivesicular bodies: ubiquitin-dependent and -independent targeting. Reggiori, F., Pelham, H.R. EMBO J. (2001) [Pubmed]
  6. Oxidative stress-induced destruction of the yeast C-type cyclin Ume3p requires phosphatidylinositol-specific phospholipase C and the 26S proteasome. Cooper, K.F., Mallory, M.J., Strich, R. Mol. Cell. Biol. (1999) [Pubmed]
  7. Analysis of the deubiquitinating enzymes of the yeast Saccharomyces cerevisiae. Amerik, A.Y., Li, S.J., Hochstrasser, M. Biol. Chem. (2000) [Pubmed]
  8. Deubiquitination step in the endocytic pathway of yeast plasma membrane proteins: crucial role of Doa4p ubiquitin isopeptidase. Dupré, S., Haguenauer-Tsapis, R. Mol. Cell. Biol. (2001) [Pubmed]
  9. 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]
  10. Role for the ubiquitin-proteasome system in the vacuolar degradation of Ste6p, the a-factor transporter in Saccharomyces cerevisiae. Loayza, D., Michaelis, S. Mol. Cell. Biol. (1998) [Pubmed]
  11. 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]
  12. Uptake of the ATP-binding cassette (ABC) transporter Ste6 into the yeast vacuole is blocked in the doa4 Mutant. Losko, S., Kopp, F., Kranz, A., Kölling, R. Mol. Biol. Cell (2001) [Pubmed]
  13. Interaction of the Doa4 deubiquitinating enzyme with the yeast 26S proteasome. Papa, F.R., Amerik, A.Y., Hochstrasser, M. Mol. Biol. Cell (1999) [Pubmed]
  14. Dual mechanisms specify Doa4-mediated deubiquitination at multivesicular bodies. Richter, C., West, M., Odorizzi, G. EMBO J. (2007) [Pubmed]
  15. The deubiquitinating enzyme Doa4p protects cells from DNA topoisomerase I poisons. Fiorani, P., Reid, R.J., Schepis, A., Jacquiau, H.R., Guo, H., Thimmaiah, P., Benedetti, P., Bjornsti, M.A. J. Biol. Chem. (2004) [Pubmed]
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