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A phosphodegron controls nutrient-induced proteasomal activation of the signaling protease Ssy5
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
2011 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 22, no 15, 2754-2765 p.Article in journal (Refereed) Published
Abstract [en]

Regulated proteolysis serves as a mechanism to control cellular processes. The SPS (Ssy1-Ptr3-Ssy5) sensor in yeast responds to extracellular amino acids by endoproteolytically activating transcription factors Stp1 and Stp2 (Stp1/2). The processing endoprotease Ssy5 is regulated via proteasomal degradation of its noncovalently associated N-terminal prodomain. We find that degradation of the prodomain requires a conserved phosphodegron comprising phosphoacceptor sites and ubiquitin-accepting lysine residues. Upon amino acid induction, the phosphodegron is modified in a series of linked events by a set of general regulatory factors involved in diverse signaling pathways. First, an amino acid-induced conformational change triggers phosphodegron phosphorylation by the constitutively active plasma membrane-localized casein kinase I (Yck1/2). Next the prodomain becomes a substrate for polyubiquitylation by the Skp1/Cullin/Grr1 E3 ubiquitin ligase complex (SCF(Grr1)). Finally, the modified prodomain is concomitantly degraded by the 26S proteasome. These integrated events are requisite for unfettering the Ssy5 endoprotease, and thus Stp1/2 processing. The Ssy5 phosphoacceptor motif resembles the Yck1/2- and Grr1-dependent degrons of regulators in the Snf3/Rgt2 glucose-sensing pathway. Our work defines a novel proteolytic activation cascade that regulates an intracellular signaling protease and illustrates how general signaling components are recruited to distinct pathways that achieve conditional and specific signaling outputs.

Place, publisher, year, edition, pages
2011. Vol. 22, no 15, 2754-2765 p.
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
URN: urn:nbn:se:su:diva-65625DOI: 10.1091/mbc.E11-04-0282ISI: 000293227200009PubMedID: 21653827OAI: oai:DiVA.org:su-65625DiVA: diva2:464289
Note

authorCount :4

Available from: 2011-12-13 Created: 2011-12-13 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Regulatory mechanisms of amino acid-induced signaling in Saccharomyces cerevisiae
Open this publication in new window or tab >>Regulatory mechanisms of amino acid-induced signaling in Saccharomyces cerevisiae
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes studies aimed at elucidating the molecular mechanisms that regulate the SPS (Ssy1-Ptr3-Ssy5) signal transduction pathway in the yeast Saccharomyces cerevisiae. This pathway is induced by extracellular amino acids and facilitates their uptake. The most downstream effectors of the SPS pathway, the homologous transcription factors Stp1 and Stp2 (Stp1/2), are synthesized as latent precursors with N-terminal regulatory domains that restrict their nuclear accumulation. Amino acid-induced signaling, initiated by the plasma membrane localized receptor Ssy1, leads via Ptr3 to the activation of the endoprotease Ssy5. Active Ssy5 cleaves the regulatory domains in Stp1/2. As a consequence, the processed transcription factors lacking their N-terminal domains accumulate in the nucleus and activate the transcription of amino acid permease genes to enhance the uptake capacity of cells.

Ssy5 is synthesized as a zymogen precursor that processes itself into a prodomain and catalytic (Cat) domain that remain non-covalently associated. We found that the prodomain functions as an inhibitor of the Cat domain. Signaling triggers the degradation of the prodomain by the proteasome, thereby releasing Cat domain activity (paper I). We identified a motif in the prodomain that functions as inducible phosphodegron. Upon signaling, this motif is phosphorylated which triggers prodomain polyubiquitylation, and as a consequence, its proteasomal degradation (paper II). Also, we found that Ptr3 functions to mediate prodomain phosphorylation upon signaling and that protein phosphatase 2A constitutively mutes phosphorylation-dependent activation of Ssy5 (paper III).

Finally, in addition to the regulation of the processing protease Ssy5, the control of transcriptional activity of Stp1 depends on a motif within its N-terminal regulatory domain, designated Region I. We found that Region I mediates latency by functioning as cytoplasmic retention determinant and nuclear degron (paper IV).

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2014. 70 p.
Keyword
Signal transduction, regulatory mechanisms, nutrient sensing, Saccharomyces cerevisiae
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-97329 (URN)978-91-7447-830-3 (ISBN)
Public defence
2014-02-04, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2014-01-13 Created: 2013-12-08 Last updated: 2014-01-02Bibliographically approved

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