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<p>Cellular quiescence is a reversible state essential for survival under nutrient-limiting or growth-restrictive conditions, yet the mechanisms fine-tuning its depth and reversibility remain elusive. Here, we identify <i>Saccharomyces cerevisiae</i> Rts3 as a regulator of the quiescence trajectory downstream of TORC1. Using phosphatase inhibitor beads and mass spectrometry, we characterize Rts3 as a phosphatase interactor in rapamycin-treated cells and define it as an inhibitor of the PP6 phosphatase Sit4. Mechanistically, it employs an α-helix to dock directly into the Sit4-Sap185/190 catalytic cleft. Transcriptionally induced by Gln3/Gat1 during nitrogen starvation, Rts3 is rapidly degraded upon nutrient repletion via a TORC1-SCF<sup>Cdc4</sup>-proteasome axis. By selectively constraining Sit4-Sap185/190 activity, this inhibitor modulates nitrogen-responsive transcriptional and translational programs to prevent excessive accumulation of Gln3/Rtg3 targets, establishing a feedback loop gating quiescence depth to support long-term survival. Our findings position Rts3 as a dynamic molecular brake on Sit4, ensuring a protective yet reversible quiescent state.</p>

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The nitrogen starvation-induced inhibitor Rts3 restrains Sit4/PP6 to gate quiescence downstream of TORC1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月26日

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  • Ladislav Dokládal,
  • Marie-Pierre Péli-Gulli,
  • Josephine Alba,
  • Michael Stumpe,
  • Malika Jaquenoud,
  • Insa Klemt,
  • Cyril Andrea Jaggi,
  • Rebecca Lourdes Calviello,
  • Zehan Hu,
  • Devanarayanan Siva Sankar,
  • Matthias Peter,
  • Jörn Dengjel,
  • Claudio De Virgilio

摘要

Cellular quiescence is a reversible state essential for survival under nutrient-limiting or growth-restrictive conditions, yet the mechanisms fine-tuning its depth and reversibility remain elusive. Here, we identify Saccharomyces cerevisiae Rts3 as a regulator of the quiescence trajectory downstream of TORC1. Using phosphatase inhibitor beads and mass spectrometry, we characterize Rts3 as a phosphatase interactor in rapamycin-treated cells and define it as an inhibitor of the PP6 phosphatase Sit4. Mechanistically, it employs an α-helix to dock directly into the Sit4-Sap185/190 catalytic cleft. Transcriptionally induced by Gln3/Gat1 during nitrogen starvation, Rts3 is rapidly degraded upon nutrient repletion via a TORC1-SCFCdc4-proteasome axis. By selectively constraining Sit4-Sap185/190 activity, this inhibitor modulates nitrogen-responsive transcriptional and translational programs to prevent excessive accumulation of Gln3/Rtg3 targets, establishing a feedback loop gating quiescence depth to support long-term survival. Our findings position Rts3 as a dynamic molecular brake on Sit4, ensuring a protective yet reversible quiescent state.