Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Aug 18;5(10):438-443.
doi: 10.15698/mic2018.10.650.

A Cinderella story: how the vacuolar proteases Pep4 and Prb1 do more than cleaning up the cell's mass degradation processes

Winnie Kerstens  1   2 , Patrick Van Dijck  1   2
Affiliations
Review

A Cinderella story: how the vacuolar proteases Pep4 and Prb1 do more than cleaning up the cell's mass degradation processes

Winnie Kerstens et al. Microb Cell. .

Abstract

Recently, several research groups have assigned non-vacuolar functions to the well-known Saccharomyces cerevisiae vacuolar proteases Pep4 and Prb1, which are also known as proteinases A and B. These non-vacuolar activities seem to be autophagy-independent and stress-induced and suggest an unexplored but possibly prominent role for the proteases outside the vacuole. The functions range from the involvement in programmed cell death, to protection from hazardous protein forms and regulation of gene expression. We propose that a deeper understanding of these molecular processes will provide new insights that will be important for both fungal biology as well as studies in mammalian cells, as they might open up perspectives in the search for novel drug targets. To illustrate this, we summarize the recent literature on non-vacuolar Pep4 and Prb1 functions in S. cerevisiae and review the current data on the protein homologs in pathogenic fungi.

Keywords: Pep4; Prb1; SAGA; Saccharomyces cerevisiae; cathepsin D; prion; programmed cell death; protease.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. FIGURE 1: Predicted locations of the Saccharomyces cerevisiae proteases Pep4 and Prb1.
Both proteases are well known for their role in protein degradation in the vacuole. Pep4 and Prb1 share a prominent role in the proteolytic activation and maturation of most vacuolar proteases, including themselves. Under stress conditions, the permeability of the vacuolar membrane has been reported to increase. This might enable the proteases to escape the vacuole and locate to other sites in the cell (indicated by arrows). It has been reported that Pep4 is associated with mitochondrial degradation under acetic acid-induced apoptosis. Furthermore, it has been described that nucleoporins are degraded by Pep4 in H2O2-induced cell death, suggesting a nucleus-associated localization. This idea is strengthened by the importance of Pep4 in the generation of the SAGA-like (SLIK) complex by cleavage of the Spt7 component of the SAGA complex. It was found that the conserved process of H3 clipping, altering gene expression, was performed by the Prb1 protease in S. cerevisiae, also suggesting a nuclear localization for Prb1. Furthermore, Prb1 was shown to inhibit [PSI+] prion formation. Okamoto et al. hypothesize that prevention of prion formation by cleavage of the Sup35 protein takes place on actively translating ribosomes. It should be noted that the non-vacuolar localizations of Pep4 and Prb1 were never confirmed in vivo by conclusive experimental results.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Müller M, Schmidt O, Angelova M, Faseri K, Weys S, Kremser L, Pfaffenwimmer T, Dalik T, Kraft C, Trajanoski Z, Lindner H, Teis D. The coordinated action of the MVB pathway and autophagy ensures cell survival during starvation. Elife. 2015;4:e07736. doi: 10.7554/eLife.07736. - DOI - PMC - PubMed
    1. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, Harper JW, Jaattela M, Johansen T, Juhasz G, Kimmelman AC, Kraft C, Ktistakis NT, Kumar S, Levine B, Lopez-Otin C. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811–1836. doi: 10.15252/embj.201796697. - DOI - PMC - PubMed
    1. Hecht KA, O'Donnell AF, Brodsky JL. The proteolytic lanscape of the yeast vacuole. Cell Logist. 2014;4(1):e28023. doi: 10.4161/cl.28023. - DOI - PMC - PubMed
    1. Woolford CA, Daniels LB, Park FJ, Jones EW, Van Arsdell JN, Innis MA. The PEP4 gene encodes an aspartyl protease implicated in the posttranslational regulation of Saccharomyces cerevisiae vacuolar hydrolases. Mol Cell Biol. 1986;6(7):2500–2510. doi: 10.1128/mcb.6.7.2500. - DOI - PMC - PubMed
    1. Van Den Hazel HB, Kielland-Brandt MC, Winther JR. Review: biosynthesis and function of yeast vacuolar proteases. Yeast. 1996;12(1):1–16. doi: 10.1002/(SICI)1097-0061(199601)12:1<1::AID-YEA902>3.0.CO;2-N. - DOI - PubMed

Grants and funding

This work was supported by a grant from the Flemish Science Foundation, FWO (project number G.0C15.14). We would like to thank Nico Vangoethem for help with the figure.

LinkOut - more resources