Iron Regulatory Mechanisms in Saccharomyces cerevisiae

Ramos-Alonso, Lucía; Romero, Antonia María; Martínez‐Pastor, María Teresa; Puig, Sergi

doi:10.3389/fmicb.2020.582830

Cited by 62 publications

(77 citation statements)

References 77 publications

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“…Applying a threshold of 2-fold (FDR < 0.05), E6/E7 mRNAs were ~4-fold upregulated in all DFO-treated conditions (Fig 3a), consistent with qRT-PCR data (Fig 1b) and other reports (30,31,33); validating the transcriptomic analyses. We found no significant change in expression of iron-dependent enzymes, a phenomenon typically observed in other systems (36), suggesting that trypanosomes have co-opted alternative mechanisms for regulating iron. Apart from TfR, the most significantly upregulated gene was an uncharacterised putative RNA Binding protein RBP5.…”

Section: Transcriptomics Identifies Iron Regulated Genes In Bsf T Bruceisupporting

confidence: 51%

“…We find that beside TfR, BSF T. brucei upregulates a cohort of trypanosome-specific genes (ESAG3, PAGS, RBP5), genes involved in glucose uptake and glycolysis (THT1 and hexokinase), endocytosis (PAP2), and most notably an RNA binding protein RBP5 (Fig 2). This finding demonstrates that post transcriptional regulation of iron responsive genes deviates from "standard" eukaryotic model systems (36), including closely related Leishmania and host cells. The significance of each of these factors is discussed below.…”

Section: Discussionmentioning

confidence: 84%

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Novel aspects of iron homeostasis in pathogenic bloodstream form Trypanosoma brucei

Carbajo

Cornell

Madbouly

et al. 2021

Preprint

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Iron is an essential regulatory signal for virulence factors in many pathogens. Mammals and bloodstream form (BSF) Trypanosoma brucei obtain iron by receptor-mediated endocytosis of transferrin bound to receptors (TfR) but the mechanisms by which T. brucei subsequently handles iron remains enigmatic. Here, we analyse the transcriptome of T. brucei cultured in iron-rich and iron-poor conditions. We show that adaptation to iron-deprivation induces upregulation of TfR, a cohort of parasite-specific genes (ESAG3, PAGS), genes involved in glucose uptake and glycolysis (THT1 and hexokinase), endocytosis (Phosphatidic Acid Phosphatase, PAP2), and most notably a divergent RNA binding protein RBP5, indicative of a non-canonical mechanism for regulating intracellular iron levels. We show that cells depleted of TfR by RNA silencing import free iron as a compensatory survival strategy. The TfR and RBP5 iron response are reversible by genetic complementation, the response kinetics are similar, but the regulatory mechanisms are distinct. Increased TfR protein is due to increased mRNA. Increased RBP5 expression, however, occurs by a post-transcriptional feedback mechanism whereby RBP5 interacts with its own, and with PAP2 mRNAs. Further observations suggest that increased RBP5 expression in iron-deprived cells has a maximum threshold as ectopic overexpression above this threshold disrupts normal cell cycle progression resulting in an accumulation of anucleate cells and cells in G2/M phase. This phenotype is not observed with overexpression of RPB5 containing a point mutation (F61A) in its single RNA Recognition Motif. Our experiments shed new light on how T. brucei BSFs reorganise their transcriptome to deal with iron stress revealing the first iron responsive RNA binding protein that is co-regulated with TfR, is important for cell viability and iron homeostasis; two essential processes for successful proliferation.

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Section: Transcriptomics Identifies Iron Regulated Genes In Bsf T Bruceisupporting

confidence: 51%

Section: Discussionmentioning

confidence: 84%

Novel aspects of iron homeostasis in pathogenic bloodstream form Trypanosoma brucei

Carbajo

Cornell

Madbouly

et al. 2021

Preprint

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“…Indeed, during iron starvation, cells are unable to grow under non-fermentable carbon sources. Iron deficiency regulation in S. cerevisiae involves metabolic remodelling, which is achieved by changes in gene expression at the transcriptional and post-transcriptional levels to prioritise iron-dependent essential cellular processes over non-essential processes, including mitochondrial respiration (reviewed in [ 62 ]). According to our previous results, we hypothesised that under iron starvation, respiratory process inhibition would also involve the down-regulation of TIF51A expression.…”

Section: Resultsmentioning

confidence: 99%

Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways

Barba‐Aliaga

Villarroel-Vicente

Stanciu

et al. 2020

IJMS

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Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types; the eIF5A-2 isoform is absent in most cells but becomes overexpressed in many metastatic cancers. Several reports have connected eIF5A and mitochondria because it co-purifies with the organelle or its inhibition reduces respiration and mitochondrial enzyme levels. However, the mechanisms of eIF5A mitochondrial function, and whether eIF5A expression is regulated by the mitochondrial metabolism, are unknown. We analysed the expression of yeast eIF5A isoforms Tif51A and Tif51B under several metabolic conditions and in mutants. The depletion of Tif51A, but not Tif51B, compromised yeast growth under respiration and reduced oxygen consumption. Tif51A expression followed dual positive regulation: by high glucose through TORC1 signalling, like other translation factors, to promote growth and by low glucose or non-fermentative carbon sources through Snf1 and heme-dependent transcription factor Hap1 to promote respiration. Upon iron depletion, Tif51A was down-regulated and Tif51B up-regulated. Both were Hap1-dependent. Our results demonstrate eIF5A expression regulation by cellular metabolic status.

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“…In S. cerevisiae , one of these additional mechanisms is mediated by the post-transcriptional factor Cth2, a protein highly expressed under iron deficiency and almost non-detectable in other growth conditions [ 10 , 11 ]. Cth2 is an RNA-binding protein, pertaining to the family of mammalian Tristetraprolin (TTP), which contains two highly conserved Cx 8 Cx 5 Cx 3 H tandem zinc fingers that specifically bind to adenosine/uridine (A/U)-rich elements (AREs) within the 3′ untranslated region (3′UTR) of many mRNAs that encode iron-containing proteins, promoting their decay and inhibiting their translation, seemingly at the initiation step [ 9 , 10 , 11 , 13 ]. Through its action, Cth2 coordinates a metabolic remodeling that allows yeast cells to prioritize the use of iron in essential processes, while other iron-dependent processes, such as respiration, are down-regulated [ 9 , 10 , 11 ].…”

Section: Iron Deficiency Impairs Translation At the Initiation Stepmentioning

confidence: 99%

“…Thus, recent studies have determined that, under short exposure to iron deficiency, yeast cells sustain global translation levels. However, if iron deprivation persists, a global translational arrest occurs at the initiation step, which is regulated by the TORC1 and Gcn2/eIF2α pathways, while the translation of a subset of messenger RNAs (mRNAs) encoding iron-containing proteins mainly involved in non-essential processes is inhibited through the post-translational regulator Cth2 [ 9 , 10 , 11 , 12 , 13 ]. We also focus on the different iron-containing proteins that participate, either directly or indirectly, in the translation process and its regulation, with special emphasis on modifications of factors affecting translational elongation (such as diphthamide modification of eEF2 and hypusination of eIF5A), post-transcriptional transfer RNA (tRNA) modifications (Elp3 and Dph3/Kti11 in the Elongator complex, wybutosine tRNA modification by Tyw1), and translational termination (Tpa1) (see Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Iron in Translation: From the Beginning to the End

2021

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Iron is an essential element for all eukaryotes, since it acts as a cofactor for many enzymes involved in basic cellular functions, including translation. While the mammalian iron-regulatory protein/iron-responsive element (IRP/IRE) system arose as one of the first examples of translational regulation in higher eukaryotes, little is known about the contribution of iron itself to the different stages of eukaryotic translation. In the yeast Saccharomyces cerevisiae, iron deficiency provokes a global impairment of translation at the initiation step, which is mediated by the Gcn2-eIF2α pathway, while the post-transcriptional regulator Cth2 specifically represses the translation of a subgroup of iron-related transcripts. In addition, several steps of the translation process depend on iron-containing enzymes, including particular modifications of translation elongation factors and transfer RNAs (tRNAs), and translation termination by the ATP-binding cassette family member Rli1 (ABCE1 in humans) and the prolyl hydroxylase Tpa1. The influence of these modifications and their correlation with codon bias in the dynamic control of protein biosynthesis, mainly in response to stress, is emerging as an interesting focus of research. Taking S. cerevisiae as a model, we hereby discuss the relevance of iron in the control of global and specific translation steps.

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Iron Regulatory Mechanisms in Saccharomyces cerevisiae

Cited by 62 publications

References 77 publications

Novel aspects of iron homeostasis in pathogenic bloodstream form Trypanosoma brucei

Novel aspects of iron homeostasis in pathogenic bloodstream form Trypanosoma brucei

Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways

Iron in Translation: From the Beginning to the End

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