Integrating Rio1 activities discloses its nutrient-activated network in Saccharomyces cerevisiae

Maria G Iacovella1, Michael Bremang1,2, Omer Basha3

  • 1Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.

Insights

The kinase Rio1 controls cell growth and division by managing a signaling network. This network impacts protein synthesis, metabolism, and cell cycle, with conserved roles in humans potentially linked to cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Saccharomyces cerevisiae Rio1 regulates crucial cellular processes including transcription, RNA processing, and ribosome biogenesis.
  • Its human ortholog, RIOK1, is implicated in tumor growth and metastasis, highlighting potential conserved roles in disease.
  • The global functions of Rio1 and its regulatory network remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the comprehensive signaling network governed by Rio1 in Saccharomyces cerevisiae.
  • To identify the direct and indirect targets and functions of Rio1 at the protein, chromatin, and RNA levels.
  • To explore the conserved functions of Rio1 and its potential implications in human diseases like cancer.

Main Methods:

  • Systematic identification of Rio1 physical interactors.
  • Global profiling of Rio1 target genes and transcripts.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to map Rio1-binding sites.
  • Integration of experimental data with existing yeast interaction databases using network computation.
  • Experimental validation of network components and subcellular localization studies.

Main Results:

  • Rio1 directly and indirectly manages an essential signaling network affecting protein, chromatin, and RNA.
  • Rio1 orchestrates cell growth and division in response to nutrient availability, parallel to the Tor1 kinase pathway.
  • The Rio1 network regulates protein synthesis, ribosome biogenesis and activity, protein turnover via the 26S proteasome, and impacts metabolic and cell-cycle programs.
  • Rio1 was localized to mitochondria and vacuoles, indicating broader cellular roles.
  • Rio1 activity and network functions are conserved in humans.

Conclusions:

  • Rio1 is a central regulator of fundamental cellular processes, including growth, division, and homeostasis, through a complex signaling network.
  • The conserved nature of Rio1 suggests its dysregulation in human cells, particularly RIOK1 in cancer, may drive pathological processes like uncontrolled proliferation and metabolic reprogramming.
  • This study provides a foundation for understanding the multifaceted roles of Rio1 and its implications in both normal physiology and disease.

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