The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1

Marie-Anne Deprez, Marco Caligaris, Joëlle Rosseels, Riko Hatakeyama, Ruben Ghillebert, Belém Sampaio-Marques, Kaivalya Mudholkar, Elja Eskes, Els Meert, Christian Ungermann, Paula Ludovico, Sabine Rospert, Claudio De Virgilio* (Corresponding Author), Joris Winderickx* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
6 Downloads (Pure)


Yeast cells maintain an intricate network of nutrient signaling pathways enabling them to integrate information on the availability of different nutrients and adjust their metabolism and growth accordingly. Cells that are no longer capable of integrating this information, or that are unable to make the necessary adaptations, will cease growth and eventually die. Here, we studied the molecular basis underlying the synthetic lethality caused by loss of the protein kinase Sch9, a key player in amino acid signaling and proximal effector of the conserved growth-regulatory TORC1 complex, when combined with either loss of the cyclin-dependent kinase (CDK) Pho85 or loss of its inhibitor Pho81, which both have pivotal roles in phosphate sensing and cell cycle regulation. We demonstrate that it is specifically the CDK-cyclin pair Pho85-Pho80 or the partially redundant CDK-cyclin pairs Pho85-Pcl6/Pcl7 that become essential for growth when Sch9 is absent. Interestingly, the respective three CDK-cyclin pairs regulate the activity and distribution of the phosphatidylinositol-3 phosphate 5-kinase Fab1 on endosomes and vacuoles, where it generates phosphatidylinositol-3,5 bisphosphate that serves to recruit both TORC1 and its substrate Sch9. In addition, Pho85-Pho80 directly phosphorylates Sch9 at Ser726, and to a lesser extent at Thr723, thereby priming Sch9 for its subsequent phosphorylation and activation by TORC1. The TORC1-Sch9 signaling branch therefore integrates Pho85-mediated information at different levels. In this context, we also discovered that loss of the transcription factor Pho4 rescued the synthetic lethality caused by loss of Pho85 and Sch9, indicating that both signaling pathways also converge on Pho4, which appears to be wired to a feedback loop involving the high-affinity phosphate transporter Pho84 that fine-tunes Sch9-mediated responses.

Original languageEnglish
Article numbere1010641
Number of pages38
JournalPLoS Genetics
Issue number2
Early online date15 Feb 2023
Publication statusPublished - 15 Feb 2023

Bibliographical note

Funding: Research was funded by fellowships of FWO-Vlaanderen (Fonds Wetenschappelijk Onderzoek) to RG and EE, a grant of the Biotechnology and Biological Sciences Research Council (BB/V016334/1) to RH, grants of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through Project-ID 403222702, SFB 1381, TP B08 to SR and RO 1028/5-2 to SR, the Germany’s Excellence Strategy, (BIOSS) EXC 949 and CIBSS (EXC 2189) to SR, the DFG projects UN111/10-2 and SFB 1557, TP14 to CU, the Swiss National Science Foundation (310030_166474/184671) to CDV, FWO-Vlaanderen (G069413, G0C7222N) to JW and KU Leuven (C14/17/063, C14/21/095) to JW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability Statement

Data Availability: All relevant data are within the manuscript and its Supporting Information files. All numerical data are included in the supplementary table: S4 Table.


Dive into the research topics of 'The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1'. Together they form a unique fingerprint.

Cite this