Gene Symbol: PEP4
Description: proteinase A
Alias: PHO9, PRA1, yscA, proteinase A
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. Teichert U, Mechler B, Muller H, Wolf D. Lysosomal (vacuolar) proteinases of yeast are essential catalysts for protein degradation, differentiation, and cell survival. J Biol Chem. 1989;264:16037-45 pubmed
    Mutants deficient in the vacuolar (lysosomal) endopeptidases proteinase yscA and proteinase yscB of the yeast Saccharomyces cerevisiae exhibit a drastically reduced protein degradation rate under nutritional stress conditions...
  2. Pereira C, Chaves S, Alves S, Salin B, Camougrand N, Manon S, et al. Mitochondrial degradation in acetic acid-induced yeast apoptosis: the role of Pep4 and the ADP/ATP carrier. Mol Microbiol. 2010;76:1398-410 pubmed publisher
    ..The finding that both mitochondrial AAC proteins and the vacuolar Pep4p interfere with mitochondrial degradation suggests a complex regulation and interplay between mitochondria and the vacuole in yeast programmed cell death...
  3. Wang S, Ng D. Evasion of endoplasmic reticulum surveillance makes Wsc1p an obligate substrate of Golgi quality control. Mol Biol Cell. 2010;21:1153-65 pubmed publisher
    ..By evading ERAD through these passive and active mechanisms, Wsc1p is fully dependent on the post-ER system for its quality control. ..
  4. Kincaid M, Cooper A. Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals. Mol Biol Cell. 2007;18:455-63 pubmed
    ..This is an important distinction for those seeking possible therapeutic approaches involving inactivating ERAD in anticipation of exporting a partially active protein. ..
  5. Westphal V, Marcusson E, Winther J, Emr S, van den Hazel H. Multiple pathways for vacuolar sorting of yeast proteinase A. J Biol Chem. 1996;271:11865-70 pubmed
    The sorting of the yeast proteases proteinase A and carboxypeptidase Y to the vacuole is a saturable, receptor-mediated process...
  6. Mehnert M, Sommer T, Jarosch E. Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nat Cell Biol. 2014;16:77-86 pubmed publisher
    ..Our data imply that Der1 initiates the export of aberrant polypeptides from the ER lumen by threading such molecules into the ER membrane and routing them to Hrd1 for ubiquitylation. ..
  7. Hsu C, Prasad R, Blackman C, Ng D. Endoplasmic reticulum stress regulation of the Kar2p/BiP chaperone alleviates proteotoxicity via dual degradation pathways. Mol Biol Cell. 2012;23:630-41 pubmed publisher
    ..Surprisingly, induced BiP/Kar2p molecules are dedicated to alleviating stress. The inability to induce KAR2 under stress had no effect on its known housekeeping functions. ..
  8. Carmona Gutierrez D, Bauer M, Ring J, Knauer H, Eisenberg T, Buttner S, et al. The propeptide of yeast cathepsin D inhibits programmed necrosis. Cell Death Dis. 2011;2:e161 pubmed publisher
    ..Thus, deletion of PEP4 resulted in both apoptotic and necrotic cell death during chronological aging...
  9. Wolff A, Petersen J, Nilsson Tillgren T, Din N. The open reading frame YAL048c affects the secretion of proteinase A in S. cerevisiae. Yeast. 1999;15:427-34 pubmed
    Over-expression of the yeast PEP4 gene encoding the vacuolar aspartic protease proteinase A (PrA) leads to saturation of the vacuolar targeting system of the cell and missorting of PrA to the growth medium...

More Information


  1. Umekawa M, Ujihara M, Makishima K, Yamamoto S, Takematsu H, Wakayama M. The signaling pathways underlying starvation-induced upregulation of α-mannosidase Ams1 in Saccharomyces cerevisiae. Biochim Biophys Acta. 2016;1860:1192-201 pubmed publisher
    ..In addition, Ams1 is post-translationally activated by Pep4-dependent processing in the vacuoles...
  2. Roberts P, Moshitch Moshkovitz S, Kvam E, O TOOLE E, Winey M, Goldfarb D. Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell. 2003;14:129-41 pubmed
    ..These results introduce a novel mode of selective microautophagy that targets nonessential components of the yeast nucleus for degradation and recycling in the vacuole. ..
  3. Marques M, Mojzita D, Amorim M, Almeida T, Hohmann S, Moradas Ferreira P, et al. The Pep4p vacuolar proteinase contributes to the turnover of oxidized proteins but PEP4 overexpression is not sufficient to increase chronological lifespan in Saccharomyces cerevisiae. Microbiology. 2006;152:3595-605 pubmed
    ..In addition to genes encoding subunits of the 20S proteasome, genes related to vacuolar proteolysis (PEP4 and LAP4), protein sorting into the vacuole, and vacuolar fusion were found to be induced...
  4. Zhang F, Gaur N, Hasek J, Kim S, Qiu H, Swanson M, et al. Disrupting vesicular trafficking at the endosome attenuates transcriptional activation by Gcn4. Mol Cell Biol. 2008;28:6796-818 pubmed publisher
  5. Song L, Chen Y, Du Y, Wang X, Guo X, Dong J, et al. Saccharomyces cerevisiae proteinase A excretion and wine making. World J Microbiol Biotechnol. 2017;33:210 pubmed publisher
    b>Proteinase A (PrA), the major protease in Saccharomyces cerevisiae, plays an essential role in zymogen activation, sporulation, and other physiological processes in vivo...
  6. 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
    ..We report that pep4 cells deficient for vacuolar protease activities accumulate vacuolar unubiquitinated Fur4p...
  7. Nair U, Jotwani A, Geng J, Gammoh N, Richerson D, Yen W, et al. SNARE proteins are required for macroautophagy. Cell. 2011;146:290-302 pubmed publisher
    ..Thus, multiple SNARE-mediated fusion events are likely to be involved in autophagosome biogenesis. ..
  8. Narayanan R, Ganesh O, Edison A, Hagen S. Kinetics of folding and binding of an intrinsically disordered protein: the inhibitor of yeast aspartic proteinase YPrA. J Am Chem Soc. 2008;130:11477-85 pubmed publisher
    ..IA 3 is an intrinsically unstructured protein that serves as an endogenous inhibitor of the yeast aspartic proteinase A (YPrA)...
  9. Theodoraki M, Nillegoda N, Saini J, Caplan A. A network of ubiquitin ligases is important for the dynamics of misfolded protein aggregates in yeast. J Biol Chem. 2012;287:23911-22 pubmed publisher
    ..These results provide insight into the mechanics by which ubiquitin ligases cooperate and provide feedback regulation in the clearance of misfolded proteins. ..
  10. Zhang H, Zhang H, Chen Q, Ruan H, Fu M, He G. Effects of proteinase A on cultivation and viability characteristics of industrial Saccharomyces cerevisiae WZ65. J Zhejiang Univ Sci B. 2009;10:769-76 pubmed publisher
    b>Proteinase A (PrA), encoded by PEP4 gene, is a key enzyme in the vacuoles of Saccharomyces cerevisiae. We characterized the effects of PrA on cell growth and glucose metabolism in the industrial S. cerevisiae WZ65...
  11. Miao Y, Han X, Zheng L, Xie Y, Mu Y, Yates J, et al. Fimbrin phosphorylation by metaphase Cdk1 regulates actin cable dynamics in budding yeast. Nat Commun. 2016;7:11265 pubmed publisher
    ..Overall, this work identifies fimbrin as a key target for cell cycle regulation of actin cable assembly in budding yeast, and suggests an underlying mechanism. ..
  12. Bryant N, Stevens T. Vacuole biogenesis in Saccharomyces cerevisiae: protein transport pathways to the yeast vacuole. Microbiol Mol Biol Rev. 1998;62:230-47 pubmed
    ..This review describes the various pathways to the vacuole and illustrates how they are related to one another in the vacuolar network of S. cerevisiae. ..
  13. Dotiwala F, Eapen V, Harrison J, Arbel Eden A, Ranade V, Yoshida S, et al. DNA damage checkpoint triggers autophagy to regulate the initiation of anaphase. Proc Natl Acad Sci U S A. 2013;110:E41-9 pubmed publisher
    ..Autophagy in response to DNA damage can be induced in three different ways: by deleting the Golgi-associated retrograde protein complex (GARP), by adding rapamycin, or by overexpression of a dominant ATG13-8SA mutation. ..
  14. Matsumoto R, Suzuki K, Ohya Y. Organelle acidification is important for localisation of vacuolar proteins in Saccharomyces cerevisiae. Protoplasma. 2013;250:1283-93 pubmed publisher
    ..These results suggest that many alterations in the localisation of vacuolar proteins occur after loss of the acidification of acidic compartments. ..
  15. Parzych K, Ariosa A, Mari M, Klionsky D. A newly characterized vacuolar serine carboxypeptidase, Atg42/Ybr139w, is required for normal vacuole function and the terminal steps of autophagy in the yeast Saccharomyces cerevisiae. Mol Biol Cell. 2018;29:1089-1099 pubmed publisher
    ..Thus, we have demonstrated that Ybr139w and Prc1 have important roles in proteolytic processing in the vacuole and the terminal steps of autophagy. ..
  16. van der Vaart A, Griffith J, Reggiori F. Exit from the Golgi is required for the expansion of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol Biol Cell. 2010;21:2270-84 pubmed publisher
    ..Our data show that the Golgi complex plays a crucial role in supplying the lipid bilayers necessary for the biogenesis of double-membrane vesicles possibly through a new class of transport carriers or a new mechanism. ..
  17. Zubenko G, Park F, Jones E. Genetic properties of mutations at the PEP4 locus in Saccharomyces cerevisiae. Genetics. 1982;102:679-90 pubmed
    Yeast cells that inherit mutations at the PEP4 locus exhibit a pronounced phenotypic lag in the expression of the mutant phenotype imparted by these mutations...
  18. Kanehara K, Xie W, Ng D. Modularity of the Hrd1 ERAD complex underlies its diverse client range. J Cell Biol. 2010;188:707-16 pubmed publisher
    ..The Hrd1 system does not directly evaluate the folding state of polypeptides. Instead, it does so indirectly, by recognizing specific embedded signals displayed upon misfolding. ..
  19. Braun S, Jentsch S. SM-protein-controlled ER-associated degradation discriminates between different SNAREs. EMBO Rep. 2007;8:1176-82 pubmed
    ..Thus, our findings identify Sly1 as a discriminating regulator of SNARE levels and indicate that Sly1-controlled ERAD might regulate the balance between different Qa-SNARE proteins. ..
  20. Mason D, Shulga N, Undavai S, Ferrando May E, Rexach M, Goldfarb D. Increased nuclear envelope permeability and Pep4p-dependent degradation of nucleoporins during hydrogen peroxide-induced cell death. FEMS Yeast Res. 2005;5:1237-51 pubmed
    ..We conclude that increases in ROS and NPC permeability occur relatively early during H(2)O(2)-induced cell death. Later, Pep4p migrates out of vacuoles and degrades nucleoporins after the cells are effectively dead. ..
  21. Bensen E, Yeung B, Payne G. Ric1p and the Ypt6p GTPase function in a common pathway required for localization of trans-Golgi network membrane proteins. Mol Biol Cell. 2001;12:13-26 pubmed
    ..Because Gos1p and Ykt6p interact with Sed5p, these results raise the possibility that TGN membrane protein localization requires Ric1p- and Ypt6p-dependent retrieval to the cis-Golgi network. ..
  22. Jensen L, Carroll M, Hall M, Harvey C, Beese S, Culotta V. Down-regulation of a manganese transporter in the face of metal toxicity. Mol Biol Cell. 2009;20:2810-9 pubmed publisher
    ..We provide evidence that manganese starvation is sensed within the lumen of the secretory pathway, whereas manganese toxicity is sensed within an extra-Golgi/cytosolic compartment of the cell. ..
  23. Swaminathan S, Sunnerhagen P. Degradation of Saccharomyces cervisiae Rck2 upon exposure of cells to high levels of zinc is dependent on Pep4. Mol Genet Genomics. 2005;273:433-9 pubmed
    ..the vacuolar proteolytic pathway with the protease inhibitor phenyl methyl sulphonyl fluoride or by mutation of the PEP4 gene...
  24. Nothwehr S, Conibear E, Stevens T. Golgi and vacuolar membrane proteins reach the vacuole in vps1 mutant yeast cells via the plasma membrane. J Cell Biol. 1995;129:35-46 pubmed
    ..We propose a model in which Vps1p is required for formation of vesicles from the late Golgi apparatus that carry vacuolar and Golgi membrane proteins bound for the prevacuolar compartment. ..
  25. Kurita T, Noda Y, Yoda K. Action of multiple endoplasmic reticulum chaperon-like proteins is required for proper folding and polarized localization of Kre6 protein essential in yeast cell wall ?-1,6-glucan synthesis. J Biol Chem. 2012;287:17415-24 pubmed publisher
    ..In conclusion, the action of multiple ER chaperon-like proteins is required for proper folding and localization of Kre6 and probably Skn1 to function in ?-1,6-glucan synthesis. ..
  26. Meussdoerffer F, Tortora P, Holzer H. Purification and properties of proteinase A from yeast. J Biol Chem. 1980;255:12087-93 pubmed
    b>Proteinase A (EC was purified from commercial bakers' yeast in five steps, including hydrophobic chromatography and affinity chromatography...
  27. Matsui A, Kamada Y, Matsuura A. The role of autophagy in genome stability through suppression of abnormal mitosis under starvation. PLoS Genet. 2013;9:e1003245 pubmed publisher
    ..Our data establish the role of autophagy in genome stability through modulation of cell division under conditions that repress cell growth. ..
  28. Spedale G, Mischerikow N, Heck A, Timmers H, Pijnappel W. Identification of Pep4p as the protease responsible for formation of the SAGA-related SLIK protein complex. J Biol Chem. 2010;285:22793-9 pubmed publisher
    ..Screening of a protease knock-out collection revealed PEP4 to be required for cleavage of Spt7p within SAGA in vitro...
  29. Shibuya A, Margulis N, Christiano R, Walther T, Barlowe C. The Erv41-Erv46 complex serves as a retrograde receptor to retrieve escaped ER proteins. J Cell Biol. 2015;208:197-209 pubmed publisher
  30. Eapen V, Haber J. DNA damage signaling triggers the cytoplasm-to-vacuole pathway of autophagy to regulate cell cycle progression. Autophagy. 2013;9:440-1 pubmed publisher
    ..These results suggest that nuclear events such as DNA damage can have profound effects on cytoplasmic processes and further expand the burgeoning connections between DNA damage and autophagy. ..
  31. 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
    ..Experiments with a doa4 pep4 double mutant showed that Ste6 uptake into the lumen of the vacuole is inhibited in the doa4 mutant...
  32. Pereira H, Azevedo F, Rego A, Sousa M, Chaves S, Corte Real M. The protective role of yeast cathepsin D in acetic acid-induced apoptosis depends on ANT (Aac2p) but not on the voltage-dependent channel (Por1p). FEBS Lett. 2013;587:200-5 pubmed publisher
    ..Our results demonstrate a differential interplay between yeast vacuolar CatD and mitochondrial proteins involved in apoptosis regulation. ..
  33. 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. ..
  34. 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 propose that Doa4 helps recycle ubiquitin from both proteasome-bound ubiquitinated intermediates and membrane proteins destined for destruction in the vacuole. ..