Lack of Maf1 enhances pyruvate kinase activity and fermentative metabolism while influencing lipid homeostasis in <i>Saccharomyces cerevisiae</i>

Mierzejewska, Jolanta; Chreptowicz, Karolina

doi:10.1002/1873-3468.12033

Cited by 16 publications

(13 citation statements)

References 29 publications

(36 reference statements)

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“…Similarly, mafr-1 (KO) animals displayed increased intracellular lipid abundance relative to age-matched WT control animals ( Fig. 1E), as expected from previous studies (Khanna et al, 2014;Mierzejewska and Chreptowicz, 2016;Palian et al, 2014;Pradhan et al, 2017). Our previous investigations revealed that overexpression of mafr-1 can influence reproductive output (Khanna et al, 2014).…”

Section: Resultssupporting

confidence: 88%

Roles for the RNA polymerase III regulator MAFR-1 in regulating sperm quality inCaenorhabditis elegans

Hammerquist

Curran

2020

Preprint

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The negative regulator of RNA polymerase (pol) III mafr-1 has been shown to affect RNA pol III transcript abundance, lipid biosynthesis and storage, progeny output, and lifespan. We deleted mafr-1 from the Caenorhabditis elegans genome and found that animals lacking mafr-1 replicated many phenotypes from previous RNAi-based studies, but strikingly not the oocyte-related reproductive phenotypes. Utilizing a yeast two-hybrid assay, we discovered several novel interactors of MAFR-1 that are expressed in a sperm-and germline-enriched manner. In support of a role for MAFR-1 in the male germline, we found mafr-1 null males have smaller spermatids that are less capable in competition for fertilization; a phenotype that was dependent on RNA pol III activity. Restoration of MAFR-1 expression specifically in the germline rescued the spermatid-related phenotypes, suggesting a cell autonomous role for MAFR-1 in nematode male fertility. Based on the high degree of conservation of Maf1 activity across species, our study may inform similar roles for Maf1 and RNA pol III in mammalian male fertility.

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Section: Resultssupporting

confidence: 88%

Roles for the RNA polymerase III regulator MAFR-1 in regulating sperm quality inCaenorhabditis elegans

Hammerquist

Curran

2020

Preprint

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“…Since rpc128-1007 grows poorly at high concentration of extracellular glucose (2%) we hypothesized that there was a lower glycolysis efficiency in the strain compared with the wild-type and maf1-Δ which in contrast displays growth inhibition on a non-fermentable carbon source but seems to metabolize glucose very efficiently when glucose is present at high concentrations [ 49 ], [ 82 ]. We verified energy status in the strains by measuring invertase activity.…”

Section: Resultsmentioning

confidence: 99%

Low RNA Polymerase III activity results in up regulation of HXT2 glucose transporter independently of glucose signaling and despite changing environment

Adamczyk

Szatkowska

2017

PLoS ONE

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BackgroundSaccharomyces cerevisiae responds to glucose availability in the environment, inducing the expression of the low-affinity transporters and high-affinity transporters in a concentration dependent manner. This cellular decision making is controlled through finely tuned communication between multiple glucose sensing pathways including the Snf1-Mig1, Snf3/Rgt2-Rgt1 (SRR) and cAMP-PKA pathways.ResultsWe demonstrate the first evidence that RNA Polymerase III (RNAP III) activity affects the expression of the glucose transporter HXT2 (RNA Polymerase II dependent—RNAP II) at the level of transcription. Down-regulation of RNAP III activity in an rpc128-1007 mutant results in a significant increase in HXT2 mRNA, which is considered to respond only to low extracellular glucose concentrations. HXT2 expression is induced in the mutant regardless of the growth conditions either at high glucose concentration or in the presence of a non-fermentable carbon source such as glycerol. Using chromatin immunoprecipitation (ChIP), we found an increased association of Rgt1 and Tup1 transcription factors with the highly activated HXT2 promoter in the rpc128-1007 strain. Furthermore, by measuring cellular abundance of Mth1 corepressor, we found that in rpc128-1007, HXT2 gene expression was independent from Snf3/Rgt2-Rgt1 (SRR) signaling. The Snf1 protein kinase complex, which needs to be active for the release from glucose repression, also did not appear perturbed in the mutated strain.Conclusions/SignificanceThese findings suggest that the general activity of RNAP III can indirectly affect the RNAP II transcriptional machinery on the HXT2 promoter when cellular perception transduced via the major signaling pathways, broadly recognized as on/off switch essential to either positive or negative HXT gene regulation, remain entirely intact. Further, Rgt1/Ssn6-Tup1 complex, which has a dual function in gene transcription as a repressor-activator complex, contributes to HXT2 transcriptional activation.

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“…Since these early studies, subsequent work in yeast has revealed that loss of Maf1 shows enlarged lipid droplets and was correlated to increased pyruvate kinase activity [18]. Moreover, a tumor suppressor function has been assigned to MAF1 [13,22], which could result from MAF1-dependent effects on lipid biosynthesis and/or RNA pol III transcription.…”

Section: Discussionmentioning

confidence: 99%

The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability

Pradhan

Hammerquist

Khanna

et al. 2017

Journal of Molecular Biology

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MAF1 is a conserved negative regulator of RNA polymerase (pol) III and intracellular lipid homeostasis across species. Here, we show that the MAF1 C-box region negatively regulates its activity. Mutations in Caenorhabditis elegans mafr-1 that truncate the C-box retain the ability to inhibit the transcription of RNA pol III targets, reduce lipid biogenesis, and lower reproductive output. In human cells, C-box deletion of MAF1 leads to increased MAF1 nuclear localization and enhanced repression of ACC1 and FASN, but with impaired repression of RNA pol III targets. Surprisingly, C-box mutations render MAF1 insensitive to rapamycin, further defining a regulatory role for this region. Two MAF1 species, MAF1L and MAF1S, are regulated by the C-box YSY motif, which, when mutated, alters species stoichiometry and proteasome-dependent turnover of nuclear MAF1. Our results reveal a role for the C-box region as a critical determinant of MAF1 stability, activity, and response to cellular stress.

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Lack of Maf1 enhances pyruvate kinase activity and fermentative metabolism while influencing lipid homeostasis in Saccharomyces cerevisiae

Cited by 16 publications

References 29 publications

Roles for the RNA polymerase III regulator MAFR-1 in regulating sperm quality inCaenorhabditis elegans

Roles for the RNA polymerase III regulator MAFR-1 in regulating sperm quality inCaenorhabditis elegans

Low RNA Polymerase III activity results in up regulation of HXT2 glucose transporter independently of glucose signaling and despite changing environment

The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability

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