Retrograde signaling is regulated by the dynamic interaction between Rtg2p and Mks1p
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Activation of retrograde signaling (RS) by mitochondrial dysfunction or by inhibition of TOR kinases in yeast results in nuclear accumulation of the transcription factors, Rtg1p and Rtg3p. This process requires Rtg2p, a novel cytoplasmic protein with an N-terminal ATP binding domain. We show that Rtg2p controls RS by reversibly binding a negative regulator, Mks1p. The inhibitory form of Mks1p is phosphorylated and complexed with the 14-3-3 proteins, Bmh1p and Bmh2p, which are also negative regulators of RS. A hypophosphorylated form of Mks1p bound to Rtg2p is inactive. Point mutations in the Rtg2p ATP binding domain simultaneously block RS and Mks1p-Rtg2p interaction. We propose that activation of RS via mitochondrial dysfunction and TOR inhibition intersect at the Rtg2p-Mks1p switch.
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Rtg2p works by binding Mks1p and promoting its dephosphorylation, which keeps it from interacting with Rtg1p and Rtg3p.
“Rtg2p works by binding the negative regulator Mks1p and promoting its dephosphorylation, which in turn keeps it from interacting with Rtg1p and Rtg3p”
From Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts (2026) · cites this paper as Liu et al. 2003
The Results report that Rtg2p binds and inactivates Mks1p, and the Discussion describes Rtg2p-bound Mks1p as hypophosphorylated. But the Discussion presents Rtg2p-mediated dephosphorylation only as a possibility, not an established mechanism. It identifies Bmh1p and Bmh2p—not Rtg1p and Rtg3p—as the proteins associated with inhibitory Mks1p; it does not support the claimed prevention of an Mks1p–Rtg1p/Rtg3p interaction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMks1p promotes the phosphorylation of Rtg3p, which inhibits the nuclear translocation of the Rtg1p/Rtg3p heterodimer.
“Mks1p promotes the phosphorylation of Rtg3p, which inhibits the nuclear translocation of the Rtg1p/Rtg3p heterodimer.”
From Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts (2026) · cites this paper as Liu et al. 2003
The Discussion (page not provided) says that keeping Rtg3p hyperphosphorylated would sequester it with Rtg1p in the cytoplasm. But it explicitly says Mks1p’s biochemical action is unknown: promoting Rtg3p phosphorylation is one proposed mechanism, alongside inhibiting an Rtg3p-directed phosphatase. The claim presents that proposed mechanism as established. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRtg2p binds the negative regulator Mks1p, which in turn keeps it from interacting with Rtg1p and Rtg3p.
“In S. cerevisiae the two proteins provide the switch that regulates the Rtg pathway by interacting with each other. Rtg2p works by binding the negative regulator Mks1p, which in turn keeps it from interacting with Rtg1p and Rtg3p (Liu et al. 2003).”
From Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts (2026) · cites this paper as Liu et al. 2003
The Discussion reports that Rtg2p regulates the yeast RTG pathway through reversible binding to the negative regulator Mks1p. The Results say this binding inactivates Mks1p; they do not support the claim that it prevents Rtg2p from interacting with Rtg1p and Rtg3p. The paper instead links pathway activation to nuclear accumulation of Rtg1p and Rtg3p. (LLM, conf=0.89)
Experimental — accuracy not yet measuredTranslocation of Rtg1p and Rtg3p to the nucleus, required for activation of the pathway, is regulated by several proteins, the key components being the negative regulator Mks1p and the positive regulator Rtg2p.
“Translocation of Rtg1p and Rtg3p to the nucleus, required for the activation of the pathway is regulated by several proteins, the key components being the negative regulator of the pathway—Mks1p, and the positive regulator Rtg2p”
From Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts (2026) · cites this paper as Liu et al. 2003
In S. cerevisiae, Rtg2p and Mks1p provide the switch that regulates the Rtg pathway by interacting with each other.
“In S. cerevisiae the two proteins provide the switch that regulates the Rtg pathway by interacting with each other. Rtg2p works by binding the negative regulator Mks1p, which in turn keeps it from interacting with Rtg1p and Rtg3p (Liu et al. 2003).”
From Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts (2026) · cites this paper as Liu et al. 2003
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References 38 · Cited by 148
Research works printed but not linked: 1
- [15]15. Komeili, A. ∙ Wedaman, K.P. ∙ O'Shea, E.K. ... Mechanism of metabolic controltarget of rapamycin signaling links nitrogen quality to the activity of the Rtg1 and Rtg3 transcription factors J. Cell Biol. 2000; 151:863-878 Crossref Scopus (186) PubMed Google Scholar
- Authors
- Liu, Z., Sekito, T., Špı́rek, M., Thornton, J., & Butow, R. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Butow, Ronald A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 12
- Issue
- 2
- Pages
- 401-411
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2090095688
- Cited by
- 148
- References
- 38
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 11 · 2023: 8 · 2022: 10 · 2021: 4 · 2020: 8 · 2019: 2 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 4 · 2014: 11 · 2013: 12 · 2012: 7
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM22525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- retrograde signaling, mitochondrial dysfunction, 14-3-3 proteins, protein phosphorylation, ATP-binding domain, negative regulation, Saccharomyces cerevisiae
- MeSH terms
- Adenosine Triphosphate, Amino Acid Sequence, beta-Galactosidase, Cloning, Molecular, Cytoplasm, Fungal Proteins, Gene Expression Regulation, Genes, Dominant, Luminescent Proteins, Microscopy, Fluorescence, Mitochondria, Models, Genetic, Molecular Sequence Data, Mutation, Phosphorylation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Transcription, Genetic, Tyrosine 3-Monooxygenase, Immunoblotting, Signal Transduction, Gene Library, Mutagenesis, Point Mutation, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Sirolimus, Saccharomyces cerevisiae Proteins, Intracellular Signaling Peptides and Proteins, 14-3-3 Proteins, Green Fluorescent Proteins
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