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The dataset is made available under the Open Database License. Any rights in individual contents of the database are licensed under the Database Contents License. Please, read the full ODbL 1.0 license text for the exact terms that apply. Users of the dataset are free to: Share: copy, distribute and use the database, either commercially or non-commercially. Create: produce derivative works from the database. Adapt: modify, transform and build upon the database. Under the following conditions: Attribution: You must attribute any public use of the database, or works produced from the database. For any use or redistribution of the database, or works produced from it, you must make clear to others the license of the original database. Share-Alike: If you publicly use any adapted version of this database, or works produced from an adapted database, you must also offer that adapted database under the ODbL, This research was funded by a predoctoral contract ACIF/2018/077 (to R.S.-D.) and grant PROMETEO/2020/014 from the Regional Government of Valencia (Generalitat Valencia-na), grant BIO2017-87828-C2-1-P and PID2020-116940RB-I00 from the Spanish Ministry of Science, Innovation and Universities, and FEDER funds (ESF, European Social Fund)., List of experimental data: Figure 2: Figure 2.xlsx Figure 2A.SC-Ura 20mM FAS.jpg Figure 2A.SC-Ura 2mM FAS.jpg Figure 2A.SC-Ura 40mM FAS.jpg Figure 2A.SC-Ura 500Fz.jpg Figure 2A.SC.jpg Figure 2C.jpg Figure 2D.jpg Figure 3: Figure 3A.SC-Ura Galactose.jpg Figure 3A.SC-Ura Galactose_1.jpg Figure 3A.SC-Ura Galactose_2.jpg Figure 3A.SC-Ura Glucose_1.jpg Figure 3A.SC-Ura Glucose_2.jpg Figure 3B.SC-Ura-Met 20mM FAS.jpg Figure 3B.SC-Ura-Met 3mM FAS.jpg Figure 3B.SC-Ura-Met 40mM FAS.jpg Figure 3B.SC-Ura-Met 5mM FAS.jpg Figure 3B.SC-Ura-Met.jpg SC-Ura glucosa.jpg Figure 4 & S1 Figure 4 & S1.xlsx Figure 5 & S2 Figure 5 & S2. Xlsx Figure 5.SC-Ura-Met 3mM FAS.Replicate 1. aGFP 10sec.jpg Figure 5.SC-Ura-Met 3mM FAS.Replicate 1. Ponceau.jpg Figure 5.SC-Ura-Met 3mM FAS.Replicate 2. aGFP 10sec.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 2. aGFP 20sec.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 2. aGFP 30sec.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 2. aPgk1.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 2. Ponceau.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 3. aGFP 10sec.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 3. aGFP 20sec.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 3. aGFP 30sec.tif Figure 5.SC-Ura-Met 3mM FAS.Replicate 3. Ponceau.jpg Figure 5.SC-Ura-Met.Replicate 1. aGFP 10sec.tif Figure 5.SC-Ura-Met.Replicate 1. aGFP 20sec.tif Figure 5.SC-Ura-Met.Replicate 1. aGFP 30sec.tif Figure 5.SC-Ura-Met.Replicate 1. Ponceau.jpg Figure 5.SC-Ura-Met.Replicate 2. aGFP 10sec.tif Figure 5.SC-Ura-Met.Replicate 2. aGFP 20sec.tif Figure 5.SC-Ura-Met.Replicate 2. aGFP 30sec.tif Figure 5.SC-Ura-Met.Replicate 2. aPgk1.tif Figure 5.SC-Ura-Met.Replicate 2. Ponceau.jpg Figure 5.SC-Ura-Met.Replicate 3. aGFP 10sec.tif Figure 5.SC-Ura-Met.Replicate 3. aGFP 20sec.tif Figure 5.SC-Ura-Met.Replicate 3. aGFP 30sec.tif Figure 5.SC-Ura-Met.Replicate 3. Ponceau.jpg Figure 6: Figure 6.PTEF2CCC1 SC-Ura-Met-3mMFAS-DIC.tif Figure 6.PTEF2CCC1 SC-Ura-Met-3mMFAS-FM4-64.tif Figure 6.PTEF2CCC1 SC-Ura-Met-3mMFAS-GFP.tif Figure 6.PTEF2CCC1 SC-Ura-Met-3mMFAS-Merge.tif Figure 6.PTEF2CCC1 SC-Ura-Met-DIC.tif Figure 6.PTEF2CCC1 SC-Ura-Met-FM4-64.tif Figure 6.PTEF2CCC1 SC-Ura-Met-GFP.tif Figure 6.PTEF2CCC1 SC-Ura-Met-Merge.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-3mMFAS-DIC.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-3mMFAS-FM4-64.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-3mMFAS-GFP.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-3mMFAS-Merge.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-DIC.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-FM4-64.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-GFP.tif Figure 6.PTEF2NtCCC1 SC-Ura-Met-Merge.tif, Peer reviewed

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in multiple metabolic processes. Iron bioavailability is highly restricted due to the low solubility of its oxidized form, frequently leading to iron deficiency anemia. The baker’s yeast Saccharomyces cerevisiae is used as a model organism for iron homeostasis studies, but also as a food supplement and fermentative microorganism in the food industry. Yeast cells use the vacuolar Ccc1 transporter to detoxify and store excess iron in the vacuoles. Here, we modulate CCC1 expression and properties to increase iron extraction from the environment. We show that constitutive expression of full-length CCC1 is toxic, whereas deletion of its cytosolic amino-terminal (Nt) domain (NtΔCCC1) rescues this phenotype. Toxicity is exacerbated in cells lacking AFT1 transcription factor. Further characterization of NtΔCcc1 protein suggests that it is a partially functional protein. Western blot analyses indicate that deletion of Ccc1 Nt domain does not significantly alter GFP-Ccc1 protein stability. A functional full-length GFP-Ccc1 protein localized to particular regions of the vacuolar membrane, whereas GFP-NtΔCcc1 protein was evenly distributed throughout this endogenous membrane. Interestingly, expression of NtΔCCC1 increased the accumulation of endogenous iron in cells cultivated under iron-sufficient conditions, a strategy that could be used to extract iron from media that are not rich in iron., This research was funded by a predoctoral contract ACIF/2018/077 (to R.S.-D.) and grant PROMETEO/2020/014 from the Regional Government of Valencia (Generalitat Valenciana), grant BIO2017-87828-C2-1-P and PID2020-116940RB-I00 from the Spanish Ministry of Science, Innovation and Universities, and FEDER funds (ESF, European Social Fund)., Peer reviewed

Iron is a vital micronutrient that functions as an essential cofactor in multiple biological processes, including oxygen transport, cellular respiration, and metabolic pathways, such as sterol biosynthesis. However, its low bioavailability at physiological pH frequently leads to nutritional iron deficiency. The yeast Saccharomyces cerevisiae is extensively used to study iron and lipid metabolisms, as well as in multiple biotechnological applications. Despite iron being indispensable for yeast ergosterol biosynthesis and growth, little is known about their interconnections. Here, we used lipid composition analyses to determine that changes in the pattern of sterols impair the response to iron deprivation of yeast cells. Yeast mutants defective in ergosterol biosynthesis display defects in the transcriptional activation of the iron-acquisition machinery and growth defects in iron-depleted conditions. The transcriptional activation function of the iron-sensing Aft1 factor is interrupted due to its mislocalization to the vacuole. These data uncover novel links between iron and sterol metabolisms that need to be considered when producing yeast-derived foods or when treating fungal infections with drugs that target the ergosterol biosynthesis pathway., This research was supported by grants BIO2017-87828-C2-1-P, PID2020-116940RB-I00, and RED2018-102467-T funded by MCIN/AEI/10.13039/501100011033 and, in the case of BIO2017-87828-C2-1-P, by ERDF A way of making Europe, and ACIF/2019/214 predoctoral fellowship funded by “Generalitat Valenciana”., Peer reviewed

Copper and iron proteins play a wide range of functions in living organisms. Metal assembly into metalloproteins is a complex process, where mismetalation is detrimental and energy-consuming to cells. Under metal deficiency, metal distribution is expected to reach a metalation ranking, prioritizing essential versus dispensable metalloproteins, while avoiding interferences with other metals and protecting metal-sensitive processes. In this review, we propose that posttranscriptional Modulators of Metalloprotein messenger RNA (ModMeR) are good candidates in metal prioritization under metal-limited conditions. ModMeR target high quota or redundant metalloproteins and, by adjusting their synthesis, ModMeR act as internal metal distribution valves. Unappropriate metalation of ModMeR targets could compete with metal delivery to essential metalloproteins and interfere with metal-sensitive processes, such as chloroplastic photosynthesis and mitochondrial respiration. Regulation of ModMeR targets could increase or decrease the metal flow through interconnected pathways in cellular metal distribution, helping to adequate differential metal requirements. Here, we describe and compare ModMeR that function in response to copper and iron deficiencies. Specifically, we describe copper-microRNAs from Arabidopsis thaliana and diverse iron ModMeR from yeast, mammals and bacteria, under copper and iron deficiencies, as well as the influence of oxidative stress. Putative functions derived from their role as ModMeR are also discussed., This work was supported by grants BIO2017-87828-C2-1-P and PID2020-116940RB-I00 funded by MCIN/AEI/10.13039/501100011033 and, in the case of BIO2017-87828-C2-1-P, by ERDF A way of making Europe., Peer reviewed

Eukaryotic cells rely on iron as an indispensable cofactor for multiple biological functions including mitochondrial respiration and protein synthesis. The budding yeast Saccharomyces cerevisiae utilizes both transcriptional and posttranscriptional mechanisms to couple mRNA levels to the requirements of iron deprivation. Thus, in response to iron deficiency, transcription factors Aft1 and Aft2 activate the expression of genes implicated in iron acquisition and mobilization, whereas two mRNA-binding proteins, Cth1 and Cth2, posttranscriptionally control iron metabolism. By using a genome-wide approach, we describe here a global stabilization of mRNAs, including transcripts encoding ribosomal proteins (RPs), when iron bioavailability diminishes. mRNA decay assays indicate that the mRNA-binding protein Pub1 contributes to RP transcript stabilization during adaptation to iron limitation. In fact, Pub1 becomes critical for growth and translational repression in low-iron conditions. Remarkably, we observe that pub1Δ cells also exhibit an increase in the transcription of RP genes that evidences the crosstalk between transcription and degradation mechanisms to maintain the appropriate mRNA balance under iron deficiency conditions., This work was supported by grants PID2020-116940RB-I00 to S. P. and RED2018-102467-T and PID2020-112853GB-C31 to J.E.P.-O., all of them funded by MCIN/AEI/10.13039/501100011033., Peer reviewed

The dataset is made available under the Open Database License. Any rights in individual contents of the database are licensed under the Database Contents License. Please, read the full ODbL 1.0 license text for the exact terms that apply. Users of the dataset are free to: Share: copy, distribute and use the database, either commercially or non-commercially. Create: produce derivative works from the database. Adapt: modify, transform and build upon the database. Under the following conditions: Attribution: You must attribute any public use of the database, or works produced from the database. For any use or redistribution of the database, or works produced from it, you must make clear to others the license of the original database. Share-Alike: If you publicly use any adapted version of this database, or works produced from an adapted database, you must also offer that adapted database under the ODbL, Ergosterol is a specific sterol component of yeast and fungal membranes. Its biosynthesis is one of the most effective targets for antifungal treatments. However, the emergent resistance to multiple sterol-based antifungal drugs emphasizes the need for new therapeutic approaches. The allylamine terbinafine, which selectively inhibits squalene epoxidase Erg1 within the ergosterol biosynthetic pathway, is mainly used to treat dermatomycoses, whereas its effectiveness in other fungal infections is limited. Given that ergosterol biosynthesis depends on iron as an essential cofactor, in this report we used the yeast Saccharomyces cerevisiae to investigate how iron bioavailability influences Erg1 expression and terbinafine susceptibility. We observed that both chemical and genetic depletion of iron decrease ERG1 expression, leading to an increase in terbinafine susceptibility. Deletion of either ROX1 transcriptional repressor or CTH1 and CTH2 post-transcriptional repressors of ERG1 expression led to an increase in Erg1 protein levels and terbinafine resistance. On the contrary, overexpression of CTH2 led to the opposite effect, lowering Erg1 levels and increasing terbinafine susceptibility. Although strain-specific particularities exist, opportunistic pathogenic strains of S. cerevisiae displayed a response similar to the laboratory strain. These data indicate that iron bioavailability and particular regulatory factors could be used to modulate susceptibility to terbinafine., This research was supported by grant PID2020-116940RB-I00 funded by MCIN/AEI/10.13039/501100011033 and predoctoral fellowship ACIF/2019/214 funded by “Generalitat Valenciana”., Peer reviewed

Ergosterol is a specific sterol component of yeast and fungal membranes. Its biosynthesis is one of the most effective targets for antifungal treatments. However, the emergent resistance to multiple sterol-based antifungal drugs emphasizes the need for new therapeutic approaches. The allylamine terbinafine, which selectively inhibits squalene epoxidase Erg1 within the ergosterol biosynthetic pathway, is mainly used to treat dermatomycoses, whereas its effectiveness in other fungal infections is limited. Given that ergosterol biosynthesis depends on iron as an essential cofactor, in this report, we used the yeast Saccharomyces cerevisiae to investigate how iron bioavailability influences Erg1 expression and terbinafine susceptibility. We observed that both chemical and genetic depletion of iron decrease ERG1 expression, leading to an increase in terbinafine susceptibility. Deletion of either ROX1 transcriptional repressor or CTH1 and CTH2 post-transcriptional repressors of ERG1 expression led to an increase in Erg1 protein levels and terbinafine resistance. On the contrary, overexpression of CTH2 led to the opposite effect, lowering Erg1 levels and increasing terbinafine susceptibility. Although strain-specific particularities exist, opportunistic pathogenic strains of S. cerevisiae displayed a response similar to the laboratory strain. These data indicate that iron bioavailability and particular regulatory factors could be used to modulate susceptibility to terbinafine., This research was supported by grant PID2020-116940RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and predoctoral fellowship ACIF/2019/214 funded by ‘Generalitat Valenciana’. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)., Peer reviewed

The dataset is made available under the Open Database License. Any rights in individual contents of the database are licensed under the Database Contents License. Please, read the full ODbL 1.0 license text for the exact terms that apply. Users of the dataset are free to: Share: copy, distribute and use the database, either commercially or non-commercially. Create: produce derivative works from the database. Adapt: modify, transform and build upon the database. Under the following conditions: Attribution: You must attribute any public use of the database, or works produced from the database. For any use or redistribution of the database, or works produced from it, you must make clear to others the license of the original database. Share-Alike: If you publicly use any adapted version of this database, or works produced from an adapted database, you must also offer that adapted database under the ODbL., Abstract: Iron is an indispensable element that participates as an essential cofactor in multiple biological processes. However, when present in excess, iron can engage in redox reactions that generaten reactive oxygen species that damage cells at multiple levels. In this report, we have characterized the response of budding yeast species from the Saccharomyces genus to elevated environmental iron concentrations. We have observed that S. cerevisiae strains are more resistant to high-iron concentra tions than Saccharomyces non-cerevisiae species. Liquid growth assays showed that species evolu tively closer to S. cerevisiae, such as S. paradoxus, S. jurei, S. mikatae, and S. arboricola were more resistant to high iron levels than the more distant species S. eubayanus and S. uvarum. Remarkably, S. kudriavzevii strains were especially iron sensitive. Growth assays in solid media suggested that S. cerevisiae and S. paradoxus were more resistant to the oxidative stress caused by elevated iron concentrations. When comparing iron accumulation and sensitivity, different patterns were observed. As previously described for S. cerevisiae, S. uvarum and particular strains of S. kudriavzevii and S. paradoxus became more sensitive to iron while accumulating more intracellular iron levels. However, no remarkable changes in intracellular iron accumulation were observed for the rest of the species. Consistent with the activation of iron detoxification systems, an increased expression of the vacuolar iron transporter CCC1 was observed for iron-sensitive strains with high endogenous iron levels. These results indicate that different mechanisms of response to elevated iron concentrations exit in the different species of the genus Saccharomyces., This research was supported by grants BIO2017-87828-C2-1-P, PID2020-116940RB-I00, and RED2018-102467-T funded by MCIN/AEI/10.13039/501100011033 and, in the case of BIO2017-87828-C2-1-P, by ERDF A way of making Europe, to S.P. Some computations were performed on Tirant III of the Spanish Supercomputing Network (‘‘Servei d’Informàtica de la Universitat de València”) under the project BCV-2021-1-0001 granted to D.P., while others were performed on resources provided by UNINETT Sigma2 - the National Infrastructure for High Performance Computing and Data Storage in Norway, project NN8029K. This work has also been supported by a predoctoral fellowship ACIF/2018/077 to R.S-D. and a predoctoral fellowship ACIF/2019/214 to T.J., both funded by “Generalitat Valenciana” and European Social Fund (ESF). D.P. is a researcher funded by the Research Council of Norway (RCN) grant Nos. RCN 324253 and Distinguished Researcher funded by the “Generalitat Valenciana” plan GenT grant No. CIDEGENT/2021/039, Peer reviewed

Iron is an indispensable element that participates as an essential cofactor in multiple biological processes. However, when present in excess, iron can engage in redox reactions that generate reactive oxygen species that damage cells at multiple levels. In this report, we characterized the response of budding yeast species from the Saccharomyces genus to elevated environmental iron concentrations. We have observed that S. cerevisiae strains are more resistant to high-iron concentrations than Saccharomyces non-cerevisiae species. Liquid growth assays showed that species evolutionarily closer to S. cerevisiae, such as S. paradoxus, S. jurei, S. mikatae, and S. arboricola, were more resistant to high-iron levels than the more distant species S. eubayanus and S. uvarum. Remarkably, S. kudriavzevii strains were especially iron sensitive. Growth assays in solid media suggested that S. cerevisiae and S. paradoxus were more resistant to the oxidative stress caused by elevated iron concentrations. When comparing iron accumulation and sensitivity, different patterns were observed. As previously described for S. cerevisiae, S. uvarum and particular strains of S. kudriavzevii and S. paradoxus became more sensitive to iron while accumulating more intracellular iron levels. However, no remarkable changes in intracellular iron accumulation were observed for the remainder of species. These results indicate that different mechanisms of response to elevated iron concentrations exist in the different species of the genus Saccharomyces., This research was supported by grants BIO2017-87828-C2-1-P, PID2020-116940RB-I00, and RED2018-102467-T funded by MCIN/AEI/10.13039/501100011033 and, in the case of BIO2017-87828-C2-1-P, by ERDF A way of making Europe, and by PROMETEO/2020/014 grant from the Regional Government of Valencia (Generalitat Valenciana). Some computations were performed on Tirant III of the Spanish Supercomputing Network (“Servei d’Informàtica de la Universitat de València”) under the project BCV-2021-1-0001 granted to D.P., while others were performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway, project NN8029K. This work has also been supported by a predoctoral fellowship ACIF/2018/077 to R.S-D. and a predoctoral fellowship ACIF/2019/214 to T.J., both funded by Generalitat Valenciana and European Social Fund (ESF). D.P. is a researcher funded by the Research Council of Norway (RCN) grant Nos. RCN 324253 and Distinguished Researcher funded by Generalitat Valenciana plan GenT grant No. CIDEGENT/2021/039., Peer reviewed

Iron participates as an essential cofactor in the biosynthesis of critical cellular components, including DNA, proteins and lipids. The ergosterol biosynthetic pathway, which is an important target of antifungal treatments, depends on iron in four enzymatic steps. Our results in the model yeast Saccharomyces cerevisiae show that the expression of ergosterol biosynthesis (ERG) genes is tightly modulated by iron availability probably through the iron-dependent variation of sterol and heme levels. Whereas the transcription factors Upc2 and Ecm22 are responsible for the activation of ERG genes upon iron deficiency, the heme-dependent factor Hap1 triggers their Tup1-mediated transcriptional repression. The combined regulation by both activating and repressing regulatory factors allows for the fine-tuning of ERG transcript levels along the progress of iron deficiency, avoiding the accumulation of toxic sterol intermediates and enabling efficient adaptation to rapidly changing conditions. The lack of these regulatory factors leads to changes in the yeast sterol profile upon iron-deficient conditions. Both environmental iron availability and specific regulatory factors should be considered in ergosterol antifungal treatments., This research was supported by grant PID2020-116940RB-I00 funded by MCIN/AEI/10.13039/501100011033 to Sergi Puig, grants PID2020-120066RB-I00 funded by MCIN/AEI/10.13039/501100011033 and AICO/2020/086 by ‘Generalitat Valenciana’ to Paula Alepuz, and grant RED2018-102467-T funded by MCIN/AEI/10.13039/501100011033 to Sergi Puig and Paula Alepuz. Tania Jordá was a recipient of a predoctoral fellowship ACIF/2019/214 funded by ‘Generalitat Valenciana’, and Marina Barba-Aliaga was a recipient of a predoctoral fellowship (FPU2017/03542) funded by MCIN/AEI/10.13039/501100011033 and by ESF Investing in your future. The authors also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)., Peer reviewed

The dataset is made available under the Open Database License. Any rights in individual contents of the database are licensed under the Database Contents License. Please, read the full ODbL 1.0 license text for the exact terms that apply. Users of the dataset are free to: Share: copy, distribute and use the database, either commercially or non-commercially. Create: produce derivative works from the database. Adapt: modify, transform and build upon the database. Under the following conditions: Attribution: You must attribute any public use of the database, or works produced from the database. For any use or redistribution of the database, or works produced from it, you must make clear to others the license of the original database. Share-Alike: If you publicly use any adapted version of this database, or works produced from an adapted database, you must also offer that adapted database under the ODbL, This work was supported by grants PID2020-116940RB-I00 and CEX2021-001189-S funded by MCIN/AEI/10.13039/501100011033. T. J. received the ACIF/2019/214 predoctoral fellowship from “Generalitat Valenciana”., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX 2021-001189-S), Peer reviewed

Sterol synthesis is an iron-dependent metabolic pathway in eukaryotes. Consequently, fungal ergosterol biosynthesis (ERG) is down-regulated in response to iron deficiency. In this report, we show that, upon iron limitation or overexpression of the iron-regulated mRNA-binding protein Cth2, the yeast Saccharomyces cerevisiae down-regulates the three initial enzymatic steps of ergosterol synthesis (ERG1, ERG7 and ERG11). Mechanistically, we show that Cth2 protein limits the translation and promotes the decrease in the mRNA levels of these specific ERG genes, which contain consensus Cth2-binding sites defined as AU-rich elements (AREs). Thus, expression of CTH2 leads to the accumulation of initial sterol intermediates, such as squalene, and to the drop of ergosterol levels. Changes in CTH2 expression levels disturb the response of yeast cells to stresses related to membrane integrity such as high ethanol and sorbitol concentrations. Therefore, CTH2 should be considered as a critical regulatory factor of ergosterol biosynthesis during iron deficiency., This work was supported by grants PID2020-116940RB-I00 and CEX2021-001189-S funded by MCIN/AEI/10.13039/501100011033. T. J. received the ACIF/2019/214 predoctoral fellowship from “Generalitat Valenciana”. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research., Peer reviewed

The dataset is made available under the Open Database License. Any rights in individual contents of the database are licensed under the Database Contents License. Please, read the full ODbL 1.0 license text for the exact terms that apply. Users of the dataset are free to: Share: copy, distribute and use the database, either commercially or non-commercially. Create: produce derivative works from the database. Adapt: modify, transform and build upon the database. Under the following conditions: Attribution: You must attribute any public use of the database, or works produced from the database. For any use or redistribution of the database, or works produced from it, you must make clear to others the license of the original database. Share-Alike: If you publicly use any adapted version of this database, or works produced from an adapted database, you must also offer that adapted database under the ODbL., This research was supported by grant PID2020-116940RB-I00 funded by MCIN/AEI/10.13039/501100011033, and PRX21/00100 Fulbright Mobility Program Fellowship from Spanish Ministerio de Universidades to S.P., Peer reviewed

Protein synthesis is a highly energy-consuming process that is downregulated in response to many environmental stresses or adverse conditions. Studies in the yeast Saccharomyces cerevisiae have shown that bulk translation is inhibited during adaptation to iron deficiency, which is consistent with its requirement for ribosome biogenesis and recycling. Although iron deficiency anemia is the most common human nutritional disorder, how iron modulates translation in mammals is poorly understood. Studies during erythropoiesis have shown that iron bioavailability is coordinated with globin synthesis via bulk translation regulation. However, little is known about the control of translation during iron limitation in other tissues. Here, we investigated how iron depletion affects protein synthesis in human osteosarcoma U-2 OS cells. By adding an extracellular iron chelator, we observed that iron deficiency limits cell proliferation, induces autophagy, and decreases the global rate of protein synthesis. Analysis of specific molecular markers indicates that the inhibition of bulk translation upon iron limitation occurs through the eukaryotic initiation factor eIF2α and mechanistic target of rapamycin (mTOR) pathways. In contrast to other environmental and nutritional stresses, iron depletion does not trigger the assembly of messenger ribonucleoprotein stress granules, which typically form upon polysome disassembly., This research was supported by grant PID2020-116940RB-I00 and CEX2021-001189-S funded by MCIN/AEI/https://doi.org/10.13039/501100011033, and PRX21/00100 Fulbright Mobility Program Fellowship from Spanish Ministerio de Universidades to S.P., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX 2021-001189-S), Peer reviewed

Iron serves as a cofactor for enzymes involved in several steps of protein translation, but the control of translation during iron limitation is not understood at the molecular level. Here, we report a genome-wide analysis of protein translation in response to iron deficiency in yeast using ribosome profiling. We show that iron depletion affects global protein synthesis and leads to translational repression of multiple genes involved in iron-related processes. Furthermore, we demonstrate that the RNA-binding proteins Cth1 and Cth2 play a central role in this translational regulation by repressing the activity of the iron-dependent Rli1 ribosome recycling factor and inhibiting mitochondrial translation and heme biosynthesis. Additionally, we found that iron deficiency represses MRS3 mRNA translation through increased expression of antisense long non-coding RNA. Together, our results reveal complex gene expression and protein synthesis remodeling in response to low iron, demonstrating how this important metal affects protein translation at multiple levels., This work was supported by NIH grants AG058713 and AG066704 to V.M.L., and grants PID2020-116940RB-I00 and CEX2021-001189-S from MCIN/AEI/10.13039/501100011033 to S.P. V.N.G. was supported by NIA grants., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX 2021-001189-S), Peer reviewed