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Cooperation of Two mRNA-Binding Proteins Drives Metabolic Adaptation to Iron Deficiency
Open accessAbstract
Iron (Fe) is an essential cofactor for a wide range of cellular processes. We have previously demonstrated in yeast that Cth2 is expressed during Fe deficiency and promotes degradation of a battery of mRNAs leading to reprogramming of Fe-dependent metabolism and Fe storage. We report here that the Cth2-homologous protein Cth1 is transiently expressed during Fe deprivation and participates in the response to Fe deficiency through the degradation of mRNAs primarily involved in mitochondrially localized activities including respiration and amino acid biosynthesis. In parallel, wild-type cells, but not cth1Deltacth2Delta cells, accumulate mRNAs encoding proteins that function in glucose import and storage and store high levels of glycogen. In addition, Fe deficiency leads to phosphorylation of Snf1, an AMP-activated protein kinase family member required for the cellular response to glucose starvation. These studies demonstrate a metabolic reprogramming as a consequence of Fe starvation that is dependent on the coordinated activities of two mRNA-binding proteins.
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“Under iron limitation, yeast cells lacking the iron-regulated RNA-binding protein Cth2 display high mRNA levels of multiple ERG genes including those of the first steps of the late stage of synthesis (ERG1, ERG7, ERG11 and DAP1) [116,118].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [118]
Citations
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“Under ironstarved conditions, Cth1 and Cth2 mediate degradation of Ccc1 mRNA (26).”
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“TheCth2andCth1proteins are also related to an “upregulation” of the mRNAs involved with glucose capture, glycolysis, and the metabolism of the carbohydrate reserve, with an increase in the expression of the mRNAs codifiers of glucose transporters and glycolytic enzymes [35].”
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The role of post-transcriptional modulators of metalloproteins in response to metal deficiencies
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“RNA- binding proteins Cth1 and Cth2 mediate the degradation of transcripts encoding iron- containing proteins or proteins that function in iron- consuming pathways in S. cerevisiae (Puig et al., 2005, 2008).”
BackgroundRomero, A. M., García‐Martínez, J., Pérez-Ortín, J. E., Martínez‐Pastor, M. T., & Puig, S. (2022) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2022.194800 · Cited by 5
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“It also includes genes encoding the mRNA binding proteins Cth1 and Cth2, which trigger the degradation of the specific mRNAs in response to Fe deficiency (Puig et al., 2008).”
BackgroundIron Starvation Response inSaccharomyces cerevisiae
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Genome-wide ribosome profiling uncovers the role of iron in the control of protein translationPreprint
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“9,10 While Cth1 and Cth2 exhibit some degree of redundancy, Cth2 plays the primary role under low iron conditions, while Cth1 exerts a fine-tuning function.”
Olgun, Ç. E., Duman, G. T., Güpür, G., İzgi, H., Huda, M., Çetin, D., Suludere, Z., Baloğlu, F. K., Çaydaşı, A. K., & Muyan, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.30.685511
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“…to RNA, Cth2 is exported to the cytoplasm, where it limits the expression of its target mRNAs by inhibiting their translation and promoting their degradation (Pedro‐Segura et al. 2008; Perea‐Garcia et al. 2020; Puig et al. 2005; Puig et al. 2008; Ramos‐Alonso et al. 2020; Vergara et al. 2011).”
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Metadata
- Authors
- Puig, S., Vergara, S. V., & Thiele, D. J.
- Affiliations
- Universitat de València (ES)
- Duke Medical Center (US)
- Corresponding author
- Puig, Sergi
- Thiele, Dennis J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 7
- Issue
- 6
- Pages
- 555-564
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2459314
- OpenAlex
- W2041968919
- Cited by
- 135
- References
- 38
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 3 · 2018: 11 · 2017: 8 · 2016: 8 · 2015: 4 · 2014: 7 · 2013: 12 · 2012: 13
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health
- U.S. Public Health Service (FDK081304A)
- National Institute of General Medical Sciences (GM 41840, R01GM041840)
- National Institute of Diabetes and Digestive and Kidney Diseases (F31DK081304)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- iron deficiency, mRNA-binding proteins, mRNA degradation, metabolic reprogramming, Snf1, AMPK, glycogen storage, mitochondrial respiration, amino acid biosynthesis, Saccharomyces cerevisiae, iron starvation response
- MeSH terms
- Iron Deficiencies, Adaptation, Physiological, DNA-Binding Proteins, Metabolism, Phosphorylation, RNA, Messenger, Saccharomyces cerevisiae, Transcription Factors, RNA-Binding Proteins, Protein Serine-Threonine Kinases, Saccharomyces cerevisiae Proteins, Tristetraprolin
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