The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1.
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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-02-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010641 |
| _version_ | 1811158380647022592 |
|---|---|
| author | 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 Joris Winderickx |
| author_facet | 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 Joris Winderickx |
| author_sort | Marie-Anne Deprez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T05:23:42Z |
| format | Article |
| id | doaj.art-71004d8ca5c847a0974bb273b721ec79 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-10T05:23:42Z |
| publishDate | 2023-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-71004d8ca5c847a0974bb273b721ec792023-03-08T05:31:00ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-02-01192e101064110.1371/journal.pgen.1010641The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1.Marie-Anne DeprezMarco CaligarisJoëlle RosseelsRiko HatakeyamaRuben GhillebertBelém Sampaio-MarquesKaivalya MudholkarElja EskesEls MeertChristian UngermannPaula LudovicoSabine RospertClaudio De VirgilioJoris WinderickxYeast 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.https://doi.org/10.1371/journal.pgen.1010641 |
| spellingShingle | 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 Joris Winderickx The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1. PLoS Genetics |
| title | The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1. |
| title_full | The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1. |
| title_fullStr | The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1. |
| title_full_unstemmed | The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1. |
| title_short | The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1. |
| title_sort | nutrient responsive cdk pho85 primes the sch9 kinase for its activation by torc1 |
| url | https://doi.org/10.1371/journal.pgen.1010641 |
| work_keys_str_mv | AT marieannedeprez thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT marcocaligaris thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT joellerosseels thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT rikohatakeyama thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT rubenghillebert thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT belemsampaiomarques thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT kaivalyamudholkar thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT eljaeskes thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT elsmeert thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT christianungermann thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT paulaludovico thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT sabinerospert thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT claudiodevirgilio thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT joriswinderickx thenutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT marieannedeprez nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT marcocaligaris nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT joellerosseels nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT rikohatakeyama nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT rubenghillebert nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT belemsampaiomarques nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT kaivalyamudholkar nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT eljaeskes nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT elsmeert nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT christianungermann nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT paulaludovico nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT sabinerospert nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT claudiodevirgilio nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 AT joriswinderickx nutrientresponsivecdkpho85primesthesch9kinaseforitsactivationbytorc1 |