Glucose intake hampers PKA-regulated HSP90 chaperone activity

Chen, Yu‐Chen; Jiang, Pei-Heng; Chen, Hsuan-Ming; Chen, Chang‐Han; Wang, Yiting; Chen, Yu‐Ju; Yu, Chia‐Jung; Teng, Shu-Chun

doi:10.7554/elife.39925

Cited by 15 publications

(6 citation statements)

References 69 publications

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“…This work and our previous findings [7] demonstrate that alterations decreasing the overall biosynthetic capabilities, protein production and size of the cell increase reproductive potential of the cell. Moreover, the results obtained with the use of the ∆hxk2 strain confirm the positive impact of low glycolytic flux and decreased PKA-activity on cell reproductive potential [7,58,59], and additionally complement the above explanations. The correlation noted between cell size and reproductive potential in the case of the ∆hxk2 strain is consistent with the hypertrophy hypothesis which assumes that cell size, and in particular the rate of cell size increase per generation, is an important regulator of the yeast cell's reproductive potential [8,39].…”

Section: Discussionsupporting

confidence: 74%

Reproductive Potential of Yeast Cells Depends on Overall Action of Interconnected Changes in Central Carbon Metabolism, Cellular Biosynthetic Capacity, and Proteostasis

Maslanka

Zadrąg‐Tęcza

2020

IJMS

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Carbon metabolism is a crucial aspect of cell life. Glucose, as the primary source of energy and carbon skeleton, determines the type of cell metabolism and biosynthetic capabilities, which, through the regulation of cell size, may affect the reproductive capacity of the yeast cell. Calorie restriction is considered as the most effective way to improve cellular physiological capacity, and its molecular mechanisms are complex and include several nutrient signaling pathways. It is widely assumed that the metabolic shift from fermentation to respiration is treated as a substantial driving force for the mechanism of calorie restriction and its influence on reproductive capabilities of cells. In this paper, we propose another approach to this issue based on analysis the connection between energy-producing and biomass formation pathways which are closed in the metabolic triangle, i.e., the respiration-glycolysis-pentose phosphate pathway. The analyses were based on the use of cells lacking hexokinase 2 (∆hxk2) and conditions of different glucose concentration corresponding to the calorie restriction and the calorie excess. Hexokinase 2 is the key enzyme involved in central carbon metabolism and is also treated as a calorie restriction mimetic. The experimental model used allows us to explain both the role of increased respiration as an effect of calorie restriction but also other aspects of carbon metabolism and the related metabolic flux in regulation of reproductive potential of the cells. The obtained results reveal that increased respiration is not a prerequisite for reproductive potential extension but rather an accompanying effect of the positive role of calorie restriction. More important seems to be the changes connected with fluxes in central carbon metabolic pathways resulting in low biosynthetic capabilities and improved proteostasis.

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Section: Discussionsupporting

confidence: 74%

Reproductive Potential of Yeast Cells Depends on Overall Action of Interconnected Changes in Central Carbon Metabolism, Cellular Biosynthetic Capacity, and Proteostasis

Maslanka

Zadrąg‐Tęcza

2020

IJMS

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“…Two phosphosites (Ser231 and Ser233) have also been detected in the C-tail of yeast Tif6, so far (Fig. S7A and S7B) [47][48][49][50][51][52] . Phosphorylation of Ser235 in the C-terminus of eIF6 has been shown to release eIF6 from the 60S 9 .…”

Section: Hdx-ms Reveals Global Changes In Eif6 Induced By Binding To ...mentioning

confidence: 87%

Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit

Elliff

Biswas

Kuppa

et al. 2022

Preprint

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Assembly of ribosomal subunits into active ribosomal complexes is integral to protein synthesis. Release of eIF6 from the 60S ribosomal subunit primes 60S to associate with the 40S subunit and engage in translation. The dynamics of eIF6 interaction with the uL14 (RPL23) interface of 60S and its regulation by somatic mutations acquired in Shwachman-Diamond Syndrome (SDS) is yet to be clearly understood. Here, by using a modified strategy to obtain high yields of recombinant human eIF6 we have uncovered the critical interface entailing 8 key residues in the C-tail of RPL23 that is essential for physical interactions between 60S and eIF6. Disruption of the complementary binding interface by conformational changes in eIF6 disease variants provide a mechanism for weakened interactions of variants with the 60S. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) analyses uncovered dynamic configurational rearrangements in eIF6 induced by binding to RPL23 and exposed an allosteric interface regulated by the C-tail of eIF6. Disrupting a key residue in the eIF6-60S binding interface markedly limits proliferation of cancer cells, which highlights the significance of therapeutically targeting this interface. Establishing these key interfaces thus provide a therapeutic framework for targeting eIF6 in cancers and SDS.

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“…We cannot discard the possibility that the CT region could be phosphorylated, as occurs in PC4 [ 4 , 56 , 57 ] or SpSub1 [ 4 , 56 , 57 ], to facilitate Sub1’s exit from the promoter and, then, regulate transcription and influence pre-mRNA processing (splicing and polyadenilation) [ 19 , 20 , 25 , 26 , 27 , 28 , 29 ]. We used the AlphaFold Protein Structure Database to predict Sub1 full length protein structure ( Figure S2 ), and we localized all the phospho-sites identified in several phospho-proteomic studies (S119, Y123, S160, S263, S268, S269, S276, and S289) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. Curiously, all phospho-residues are within the CT region: two of them are near the ssDBD, and five of them are in the most C-terminal region of the protein.…”

Section: Discussionmentioning

confidence: 99%

The Role of S. cerevisiae Sub1/PC4 in Transcription Elongation Depends on the C-Terminal Region and Is Independent of the ssDNA Binding Domain

Collin

González-Jiménez

et al. 2022

Cells

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Saccharomyces cerevisiae Sub1 (ScSub1) has been defined as a transcriptional stimulatory protein due to its homology to the ssDNA binding domain (ssDBD) of human PC4 (hPC4). Recently, PC4/Sub1 orthologues have been elucidated in eukaryotes, prokaryotes, and bacteriophages with functions related to DNA metabolism. Additionally, ScSub1 contains a unique carboxyl–terminal region (CT) of unknown function up to date. Specifically, it has been shown that Sub1 is required for transcription activation, as well as other processes, throughout the transcription cycle. Despite the progress that has been made in understanding the mechanism underlying Sub1′s functions, some questions remain unanswered. As a case in point: whether Sub1’s roles in initiation and elongation are differentially predicated on distinct regions of the protein or how Sub1′s functions are regulated. Here, we uncover some residues that are key for DNA–ScSub1 interaction in vivo, localized in the ssDBD, and required for Sub1 recruitment to promoters. Furthermore, using an array of genetic and molecular techniques, we demonstrate that the CT region is required for transcription elongation by RNA polymerase II (RNAPII). Altogether, our data indicate that Sub1 plays a dual role during transcription—in initiation through the ssDBD and in elongation through the CT region.Sub1; PC4; DNA binding proteins; RNA polymerase II; transcription elongation; Saccharomyces cerevisiae

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Glucose intake hampers PKA-regulated HSP90 chaperone activity

Cited by 15 publications

References 69 publications

Reproductive Potential of Yeast Cells Depends on Overall Action of Interconnected Changes in Central Carbon Metabolism, Cellular Biosynthetic Capacity, and Proteostasis

Reproductive Potential of Yeast Cells Depends on Overall Action of Interconnected Changes in Central Carbon Metabolism, Cellular Biosynthetic Capacity, and Proteostasis

Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit

The Role of S. cerevisiae Sub1/PC4 in Transcription Elongation Depends on the C-Terminal Region and Is Independent of the ssDNA Binding Domain

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