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Tum1 Is Involved in the Metabolism of Sterol Esters in Saccharomyces Cerevisiae Katja Uršič1,4, Mojca Ogrizović1,Dušan Kordiš1, Klaus Natter2 and Uroš Petrovič1,3*

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Tum1 Is Involved in the Metabolism of Sterol Esters in Saccharomyces Cerevisiae Katja Uršič1,4, Mojca Ogrizović1,Dušan Kordiš1, Klaus Natter2 and Uroš Petrovič1,3* Uršič et al. BMC Microbiology (2017) 17:181 DOI 10.1186/s12866-017-1088-1 RESEARCHARTICLE Open Access Tum1 is involved in the metabolism of sterol esters in Saccharomyces cerevisiae Katja Uršič1,4, Mojca Ogrizović1,Dušan Kordiš1, Klaus Natter2 and Uroš Petrovič1,3* Abstract Background: The only hitherto known biological role of yeast Saccharomyces cerevisiae Tum1 protein is in the tRNA thiolation pathway. The mammalian homologue of the yeast TUM1 gene, the thiosulfate sulfurtransferase (a.k.a. rhodanese) Tst, has been proposed as an obesity-resistance and antidiabetic gene. To assess the role of Tum1 in cell metabolism and the putative functional connection between lipid metabolism and tRNA modification, we analysed evolutionary conservation of the rhodanese protein superfamily, investigated the role of Tum1 in lipid metabolism, and examined the phenotype of yeast strains expressing the mouse homologue of Tum1, TST. Results: We analysed evolutionary relationships in the rhodanese superfamily and established that its members are widespread in bacteria, archaea and in all major eukaryotic groups. We found that the amount of sterol esters was significantly higher in the deletion strain tum1Δ than in the wild-type strain. Expression of the mouse TST protein in the deletion strain did not rescue this phenotype. Moreover, although Tum1 deficiency in the thiolation pathway was complemented by re-introducing TUM1, it was not complemented by the introduction of the mouse homologue Tst. We further showed that the tRNA thiolation pathway is not involved in the regulation of sterol ester content in S. cerevisiae,asoverexpressionofthetEUUC,tKUUU and tQUUG tRNAs did not rescue the lipid phenotype in the tum1Δ deletion strain, and, additionally, deletion of the key gene for the tRNA thiolation pathway, UBA4, did not affect sterol ester content. Conclusions: The rhodanese superfamily of proteins is widespread in all organisms, and yeast TUM1 is a bona fide orthologue of mammalian Tst thiosulfate sulfurtransferase gene. However, the mouse TST protein cannot functionally replace yeast Tum1 protein, neither in its lipid metabolism-related function, nor in the tRNA thiolation pathway. We show here that Tum1 protein is involved in lipid metabolism by decreasing the sterol ester content in yeast cells, and that this function of Tum1 is not exerted through the tRNA thiolation pathway, but through another, currently unknown pathway. Keywords: Lipid metabolism, tRNA modification, Yeast Saccharomyces cerevisiae Background to have obesity-resistance and anti-diabetes effects in Lipids are important dynamic molecules that play vital mammals [7]. The mechanism of action causing the de- roles, which extend beyond their structural roles in creased accumulation of storage lipids was proposed to cellular membranes [1–4]. Lipid metabolism has lately be increased expression and activity of the protein, gained much attention in particular due to its role in resulting in augmented mitochondrial function and in- health and disease, especially in the emerging pandemics creased degradation of reactive oxygen species and of obesity and type 2 diabetes [5, 6]. Recently, mouse sulfide. thiosulfate sulfurtransferase (TST) protein was proposed TUM1 (YOR251c) is a unique yeast Saccharomyces cerevisiae ortholog of the human TST gene [8]. Tum1 and TST/MPST (mercaptopyruvate sulfurtransferase) * Correspondence: [email protected] 1Jožef Stefan Institute, Department of Molecular and Biomedical Sciences, proteins belong to the rhodanese/cell cycle control phos- Jamova cesta 39, 1000 Ljubljana, Slovenia phatase protein superfamily. The rhodanese superfamily 3 Biotechnical Faculty, Department of Biology, University of Ljubljana, Večna contains the fold with the same name and the proteins pot 111, 1000 Ljubljana, Slovenia Full list of author information is available at the end of the article from this superfamily span a wide range of molecular © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Uršič et al. BMC Microbiology (2017) 17:181 Page 2 of 9 functions. In this study we examined the molecular role method [23] and the neighbor-joining method [24]. The of the yeast Tum1 protein which has been previously de- reliability of the resulting topologies was tested by the scribed only as a protein with a non-essential function in bootstrap method. Two archaeal rhodanese superfamily the tRNA wobble uridine modification pathway [9, 10]. representatives were used as the outgroup in the global This pathway consists also of Uba4, Ncs2, Ncs6 and rhodanese phylogeny, while the Arabidopsis TST1 repeat Nfs1 proteins and is required for the thiolation of three domain of rhodanese protein was used to root the tRNA molecules, specific for glutamine (tQUUG), lysine Opisthokonta rhodanese tree. Phylogenetic analyses were (tKUUU), and glutamic acid (tEUUC) tRNAs, which con- performed with IQ Tree web server [22]. tain 2-thiouridine derivate as the wobble nucleoside [11]. To date, 156 genes have been annotated to lipid Synteny analysis of the rhodanese superfamily in metabolism in S. cerevisiae [12] and additional proteins vertebrates are still being described as involved in this complex For synteny analyses, the chromosomal locations, lengths, process [4]. However, no functional connection between and the directionality of the neighbouring genes upstream tRNA modification and lipid metabolism has been estab- and downstream of Tst and Mpst genes were extracted lished yet, opening a question of structural and func- from Ensembl [25] and Entrez [26] genome databases. tional conservation of the rhodanese superfamily Additional synteny comparisons were conducted using members in general, and Tum1 and TST in particular. Genomicus [27]. We therefore analysed evolutionary conservation of the rhodanese protein superfamily, investigated the role of Strains and media Tum1 in lipid metabolism, and examined the putative The Saccharomyces cerevisiae wild-type (WT) strain functional connection between lipid metabolism and BY4741 (MATa his3Δ1 leu2Δ0 met15Δ ura3Δ0) and the tRNA modification processes. isogenic uba4Δ deletion strain were obtained from the EUROSCARF strain collection. The tum1Δ deletion Methods strain was constructed by replacing the TUM1 open Sequence data mining reading frame (ORF) with the KanMX resistance cas- All database searches were performed online. The data- sette. A strain with re-inserted TUM1 was used as the bases analysed were the prokaryotic and eukaryotic pro- control strain. The ORF of the Tst gene was PCR- tein, transcriptome and genome databases at the amplified from the appropriate mouse (Mus musculus) National Center for Biotechnology Information [13]. To cDNA clone and introduced into the TUM1 locus, under detect all available representatives of the rhodanese the control of the endogenous yeast promoter. superfamily, database searches were performed iteratively. Strains were grown in rich medium YPD (2% peptone, Comparisons were performed using the TBLASTN pro- 1% yeast extract, 2% glucose) or in synthetic complete − gram [14], with the E-value cutoff set to 10 5 and default medium lacking uracil (SC-Ura). YPD plates containing settings for other parameters. Diverse prokaryotic and 0.5 mg/ml geneticin (G418, Formedium) or 0.1 mg/ml eukaryotic representatives of the rhodanese superfamily nourseothricin (clonNAT, Werner) were used to select [15, 16] have been used as queries. The Translate program for geneticin or nourseothricin resistance. from Expasy [17] was used to translate DNA sequences. Plasmid construction Phylogenetic analysis DNA manipulations, plasmid preparations and bacterial Eukaryotic and prokaryotic representatives of the rhoda- transformations were performed according to standard nese superfamily [15, 16] were included in the analyses. methods. For expression of TUM1 or Tst under control Diverse opisthokont representatives of the rhodanese of the ADH1 promoter, the respective ORFs were superfamily were also included in the separate analysis. inserted into the pUG35 plasmid backbone [28] immedi- The rhodanese domain in the newly discovered repre- ately after the ADH1 promoter. Plasmids were named sentatives of the rhodanese superfamily was identified by according to inserts: [empty] for backbone only, [TUM1] using the SMART [18], InterPro [19] and Pfam [20] do- for the plasmid expressing yeast TUM1 and [Tst] for the main databases. The protein sequences were aligned plasmid expressing mouse Tst. using Clustal Omega [21]. We used IQ Tree web server Plasmids pABY1653 (tEUUC-tKUUU-tQUUG)andpABY525 [22] to select the best maximum likelihood model of se- (control), described in [29], were kindly provided by quence evolution for the data from the rhodanese super- Prof. Anders Byström, Umeå University, Sweden. family. The best fit model of amino acid substitution for our data set was determined as LG + G4 according to Isolation and purification of tRNA BIC (Bayesian information criterion). Phylogenetic trees
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