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

Abstract

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.

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

“…Using yeasts that expressed the two yeast eIF5A analogs Tif51A and Tif51B Barba-aliaga et al [ 80 ] analysed how eIF5A expression is regulated to adapt yeast to the metabolic requirements. They observed that only the isoform Tif51A and not Tif51B, is needed for growth in the presence of glycerol and ethanol as carbon sources.…”

Iron in Translation: From the Beginning to the End

“…Surprisingly, yeast lia1∆ mutants are viable, which suggests that the deoxyhypusinated form of eIF5A is partially functional in yeast, as has been demonstrated for at least some eIF5A functions [ 102 , 103 ]. In fact, only deoxyhypusine-eIF5A, but not hypusine-eIF5A, is found in yeast lia1∆ mutants, which indicates that the deoxyhypusine form can support growth [ 19 , 104 ]. Still, lia1∆ mutants are unable to form shmoos in the presence of the alpha-mating factor, suggesting that the complete hypusination process is necessary for some eIF5A-dependent functions [ 87 ].…”

“…Early studies centered on the influence of oxygen and heme levels over eIF5A expression, showing a reciprocal regulation where TIF51B mRNA levels increase in anaerobiosis, whereas TIF51A expression is up-regulated during aerobiosis [ 78 , 105 , 106 ]. More recent studies have shown that LIA1 mRNA levels also increase in anaerobiosis and that TIF51A , but not TIF51B , is required for growth under respiratory conditions, and its depletion reduces oxygen consumption [ 104 , 107 ]. Interestingly, full eIF5A hypusination is not required for maintaining high respiratory levels.…”

“…TIF51A expression is regulated by TORC1 signaling under high glucose, and by Snf1 and the heme-dependent factor Hap1 under low glucose and respiratory conditions, respectively. Upon iron depletion, TIF51A and LIA1 are down-regulated, whereas TIF51B is up-regulated, in a Hap1-dependent manner [ 12 , 104 ]. Several global expression studies in the pathogenic yeast Candida glabrata confirm the down-regulation of the corresponding Cg LIA1 homolog under iron deficiency (reviewed in [ 108 , 109 ]).…”

Hypusination, a Metabolic Posttranslational Modification of eIF5A in Plants during Development and Environmental Stress Responses

“…It can be concluded that AteIF5A-3 has a more dominant role in nutrient and hormone translocation than in cell division [ 5 ]. In yeasts, Barba-Aliaga et al (2020) [ 74 ] described the different regulation activities of eIF5A isoforms during iron starvation, as eIF5A-1 was downregulated while eIF5A-2 was upregulated. Under Fe-deficient conditions, a generally decreased abundance of ribosomal proteins was investigated.…”