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Gene Review

PEP4  -  Pep4p

Saccharomyces cerevisiae S288c

Synonyms: Aspartate protease, Carboxypeptidase Y-deficient protein 4, P2585, PHO9, PRA1, ...
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Disease relevance of PEP4

  • Two were pepstatin-sensitive carboxyl proteinases (porcine pepsin and proteinase A from baker's yeast) and two were pepstatin-insensitive carboxyl proteinases (from Pseudomonas sp. 101 (pseudomonapepsin; PCP) and Xanthomonas sp. T-22 (xanthomonapepsin; XCP)) [1].
  • The toxicity of HBsAg in the secretion pathway of pep4 strains can be progressively reduced in modified SD media containing lower concentrations of ammonium sulphate [2].
  • Previously we reported a procedure to enrich NI transformants that are not inhibited by cytotoxic expression of hepatitis B virus surface antigen in the secretion pathway of the protease-A-deficient (pep4) strain [3].

High impact information on PEP4

  • The vps34 and vps15 mutants displayed additional phenotypes such as defects in transport of proteinase A and proteinase B, implying the existence of another PtdIns 3-kinase complex(es) [4].
  • Efficient proCPY maturation was possible when donor membranes were from a yeast strain deleted for the PEP4 gene (which encodes the principal CPY processing enzyme, proteinase A) and acceptor membranes from a PEP4 yeast strain, indicating intercompartmental transfer [5].
  • Chs2p degradation depends on the vacuolar protease encoded by PEP4, indicating that Chs2p is destroyed in the vacuole [6].
  • However, yeast mutant strains defective in endocytosis (end3, end4 and chc1-ts) and vacuolar degradation (pep4) exhibit copper-dependent Ctr1p degradation, indicating that internalization and delivery to the vacuole is not the principal mechanism responsible for degradation [7].
  • NOP4 is a single copy essential gene present on chromosome XVI, between RAD1 and PEP4 [8].

Biological context of PEP4


Anatomical context of PEP4

  • These mutant fusion proteins were then delivered directly from a late Golgi compartment to the vacuole, where they were proteolytically cleaved in a PEP4-dependent manner [13].
  • When the 22 degrees C culture was shifted to 34 degrees C, Ste2-3p was removed from the plasma membrane and degraded by a PEP4-dependent mechanism with a 24-min half-life; the wild-type Ste2p displayed a 72-min half-life [14].
  • Stimulation of in vitro processing with energy and cytosol took place efficiently when the expression of PEP4, under control of the GAL1 promoter, was induced then completely repressed before radiolabeling spheroplasts [15].
  • We found that the 76-amino-acid preprosegment of PrA contains at least two sorting signals: an amino-terminal signal peptide that is cleaved from the protein at the level of the endoplasmic reticulum followed by the prosegment which functions as a vacuolar protein-sorting signal [16].
  • These vat mutant strains accumulate and secrete precursor forms of the soluble vacuolar hydrolases carboxypeptidase Y and proteinase A. The kinetics of secretion suggests that missorting occurs in the Golgi complex or in post-Golgi vesicles [17].

Associations of PEP4 with chemical compounds

  • When a multicopy PEP4 transformant of a prb1 mutant was grown in the presence of the aspartyl protease inhibitor pepstatin A, a significant level of proPrA was found in the growth medium [18].
  • This degradation is blocked by inhibiting the vacuolar proteolytic pathway with the protease inhibitor phenyl methyl sulphonyl fluoride or by mutation of the PEP4 gene [19].
  • One of these activities was a PEP4-dependent carboxypeptidase that was sensitive to phenylmethylsulfonyl fluoride [20].
  • Proteinase yscA deficiency leads to rapid cell death when glucose-grown cells starve for nitrogen or other nutrients [21].
  • We investigated the relationship between acidification and protein sorting in yeast by treating yeast cells with ammonium chloride and found that this lysosomotropic agent caused the mislocalization of a substantial fraction of the newly synthesized vacuolar (lysosomal) enzyme proteinase A (PrA) to the cell surface [22].

Physical interactions of PEP4


Regulatory relationships of PEP4


Other interactions of PEP4

  • Degradation was not observed in strains defective in the END3/END4 endocytic pathway or in the production of vacuolar proteases (PEP4) [28].
  • In cells with a deletion in the vacuolar protease PEP4, high iron medium leads to the accumulation of Fet3p and Ftr1p in the vacuole [29].
  • Both PEP4 or PRC1 gene disruptions resulted in a lower frequency of mitochondrial DNA escape [30].
  • However, mature proteinase yscB is not stable in the absence of proteinase yscA [31].
  • Additional mutations in the carboxy-terminus of Vps10p, including a deletion of a putative retention/recycling signal (FYVF), also result in CPY missorting and PEP4-dependent receptor instability [32].

Analytical, diagnostic and therapeutic context of PEP4


  1. Effects of pressure on the activity and spectroscopic properties of carboxyl proteinases. Apparent correlation of pepstatin-insensitivity and pressure response. Fujiwara, S., Kunugi, S., Oyama, H., Oda, K. Eur. J. Biochem. (2001) [Pubmed]
  2. Abnormal growth induced by expression of HBsAg in the secretion pathway of S. cerevisiae pep4 mutants. Chen, D.C., Chuang, L.T., Chen, W.P., Kuo, T.T. Curr. Genet. (1995) [Pubmed]
  3. A variant of Saccharomyces cerevisiae pep4 strain with improved oligotrophic proliferation, cell survival and heterologous secretion of alpha-amylase. Chen, D.C., Chen, S.Y., Gee, M.F., Pan, J.T., Kuo, T.T. Appl. Microbiol. Biotechnol. (1999) [Pubmed]
  4. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. Kihara, A., Noda, T., Ishihara, N., Ohsumi, Y. J. Cell Biol. (2001) [Pubmed]
  5. A cell-free assay allows reconstitution of Vps33p-dependent transport to the yeast vacuole/lysosome. Vida, T., Gerhardt, B. J. Cell Biol. (1999) [Pubmed]
  6. Differential trafficking and timed localization of two chitin synthase proteins, Chs2p and Chs3p. Chuang, J.S., Schekman, R.W. J. Cell Biol. (1996) [Pubmed]
  7. Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis. Ooi, C.E., Rabinovich, E., Dancis, A., Bonifacino, J.S., Klausner, R.D. EMBO J. (1996) [Pubmed]
  8. The yeast NOP4 gene product is an essential nucleolar protein required for pre-rRNA processing and accumulation of 60S ribosomal subunits. Sun, C., Woolford, J.L. EMBO J. (1994) [Pubmed]
  9. A novel aspartyl protease allowing KEX2-independent MF alpha propheromone processing in yeast. Egel-Mitani, M., Flygenring, H.P., Hansen, M.T. Yeast (1990) [Pubmed]
  10. Mapping of the trifunctional fatty acid synthetase gene FAS2 on chromosome XVI of Saccharomyces cerevisiae. Siebenlist, U., Nix, J., Schweizer, M., Jäger, D., Schweizer, E. Yeast (1990) [Pubmed]
  11. Construction of protease-deficient Candida boidinii strains useful for recombinant protein production: cloning and disruption of proteinase A gene (PEP4) and proteinase B gene (PRBI). Komeda, T., Sakai, Y., Kato, N., Kondo, K. Biosci. Biotechnol. Biochem. (2002) [Pubmed]
  12. Biogenesis of the yeast vacuole (lysosome). Active site mutation in the vacuolar aspartate proteinase yscA blocks maturation of vacuolar proteinases. Rupp, S., Hirsch, H.H., Wolf, D.H. FEBS Lett. (1991) [Pubmed]
  13. Signal-mediated retrieval of a membrane protein from the Golgi to the ER in yeast. Gaynor, E.C., te Heesen, S., Graham, T.R., Aebi, M., Emr, S.D. J. Cell Biol. (1994) [Pubmed]
  14. Elimination of defective alpha-factor pheromone receptors. Jenness, D.D., Li, Y., Tipper, C., Spatrick, P. Mol. Cell. Biol. (1997) [Pubmed]
  15. In vitro reconstitution of intercompartmental protein transport to the yeast vacuole. Vida, T.A., Graham, T.R., Emr, S.D. J. Cell Biol. (1990) [Pubmed]
  16. Intracellular sorting and processing of a yeast vacuolar hydrolase: proteinase A propeptide contains vacuolar targeting information. Klionsky, D.J., Banta, L.M., Emr, S.D. Mol. Cell. Biol. (1988) [Pubmed]
  17. Compartment acidification is required for efficient sorting of proteins to the vacuole in Saccharomyces cerevisiae. Klionsky, D.J., Nelson, H., Nelson, N. J. Biol. Chem. (1992) [Pubmed]
  18. Vacuolar and extracellular maturation of Saccharomyces cerevisiae proteinase A. Wolff, A.M., Din, N., Petersen, J.G. Yeast (1996) [Pubmed]
  19. Degradation of Saccharomyces cervisiae Rck2 upon exposure of cells to high levels of zinc is dependent on Pep4. Swaminathan, S., Sunnerhagen, P. Mol. Genet. Genomics (2005) [Pubmed]
  20. Endoproteolytic processing of a farnesylated peptide in vitro. Ashby, M.N., King, D.S., Rine, J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  21. Lysosomal (vacuolar) proteinases of yeast are essential catalysts for protein degradation, differentiation, and cell survival. Teichert, U., Mechler, B., Müller, H., Wolf, D.H. J. Biol. Chem. (1989) [Pubmed]
  22. Acidification of the lysosome-like vacuole and the vacuolar H+-ATPase are deficient in two yeast mutants that fail to sort vacuolar proteins. Rothman, J.H., Yamashiro, C.T., Raymond, C.K., Kane, P.M., Stevens, T.H. J. Cell Biol. (1989) [Pubmed]
  23. 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]
  24. Catabolite inactivation of the high-affinity hexose transporters Hxt6 and Hxt7 of Saccharomyces cerevisiae occurs in the vacuole after internalization by endocytosis. Krampe, S., Stamm, O., Hollenberg, C.P., Boles, E. FEBS Lett. (1998) [Pubmed]
  25. Maturation of vacuolar (lysosomal) enzymes in yeast: proteinase yscA and proteinase yscB are catalysts of the processing and activation event of carboxypeptidase yscY. Mechler, B., Müller, H., Wolf, D.H. EMBO J. (1987) [Pubmed]
  26. Formation of a complex between yeast proteinases A and B. Hinze, H., Betz, H., Saheki, T., Holzer, H. Hoppe-Seyler's Z. Physiol. Chem. (1975) [Pubmed]
  27. Interaction of proteinases and their inhibitors from yeast. Activation of carboxypeptidase Y. Fischer, E.P., Holzer, H. Biochim. Biophys. Acta (1980) [Pubmed]
  28. Regulation of inositol transport in Saccharomyces cerevisiae involves inositol-induced changes in permease stability and endocytic degradation in the vacuole. Lai, K., Bolognese, C.P., Swift, S., McGraw, P. J. Biol. Chem. (1995) [Pubmed]
  29. Post-transcriptional regulation of the yeast high affinity iron transport system. Felice, M.R., De Domenico, I., Li, L., Ward, D.M., Bartok, B., Musci, G., Kaplan, J. J. Biol. Chem. (2005) [Pubmed]
  30. Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments. Campbell, C.L., Thorsness, P.E. J. Cell. Sci. (1998) [Pubmed]
  31. Biogenesis of the yeast vacuole (lysosome). The use of active-site mutants of proteinase yscA to determine the necessity of the enzyme for vacuolar proteinase maturation and proteinase yscB stability. Rupp, S., Wolf, D.H. Eur. J. Biochem. (1995) [Pubmed]
  32. The cytoplasmic tail domain of the vacuolar protein sorting receptor Vps10p and a subset of VPS gene products regulate receptor stability, function, and localization. Cereghino, J.L., Marcusson, E.G., Emr, S.D. Mol. Biol. Cell (1995) [Pubmed]
  33. The PEP4 gene encodes an aspartyl protease implicated in the posttranslational regulation of Saccharomyces cerevisiae vacuolar hydrolases. Woolford, C.A., Daniels, L.B., Park, F.J., Jones, E.W., Van Arsdell, J.N., Innis, M.A. Mol. Cell. Biol. (1986) [Pubmed]
  34. Characterization of proteinase A glycoforms from recombinant Saccharomyces cerevisiae. Pedersen, J., Biedermann, K. Biotechnol. Appl. Biochem. (1993) [Pubmed]
  35. Characterization of genes required for protein sorting and vacuolar function in the yeast Saccharomyces cerevisiae. Rothman, J.H., Howald, I., Stevens, T.H. EMBO J. (1989) [Pubmed]
  36. 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]
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