Multiple Layers of Phospho-Regulation Coordinate Metabolism and the Cell Cycle in Budding Yeast

Zhang, Lichao; Winkler, Sebastian; Schlottmann, Fabian; Kohlbacher, Oliver; Elias, Joshua E.; Skotheim, Jan M.; Ewald, Jennifer C.

doi:10.3389/fcell.2019.00338

Cited by 27 publications

(16 citation statements)

References 77 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The multi‐directional coordination of the cell division machinery, metabolism, and cell growth (the accumulation of mass) is essential for cell division [ 4 ] (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies in this past decade have challenged the view that there is a hierarchy of metabolism and growth over the cell division cycle [ 4 ]. Indeed, several core cell cycle regulators and components, notably cyclin D, CDKs, pRB and E2Fs, specifically target metabolic enzymes and pathways and thereby control metabolism and growth [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

et al. 2020

View full text Add to dashboard Cite

Adapting to changes in nutrient availability and environmental conditions is a fundamental property of cells. This adaptation requires a multi-directional coordination between metabolism, growth, and the cell cycle regulators (consisting of the family of cyclin-dependent kinases (CDKs), their regulatory subunits known as cyclins, CDK inhibitors, the retinoblastoma family members, and the E2F transcription factors). Deciphering the mechanisms accountable for this coordination is crucial for understanding various patho-physiological processes. While it is well established that metabolism and growth affect cell division, this review will focus on recent observations that demonstrate how cell cycle regulators coordinate metabolism, cell cycle progression, and growth. We will discuss how the cell cycle regulators directly regulate metabolic enzymes and pathways and summarize their involvement in the endolysosomal pathway and in the functions and dynamics of mitochondria.

show abstract

“…The multi‐directional coordination of the cell division machinery, metabolism, and cell growth (the accumulation of mass) is essential for cell division [ 4 ] (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

et al. 2020

View full text Add to dashboard Cite

show abstract

“…3). This could be caused by two (not mutually exclusive) mechanisms: firstly, there could be a minor increase in PKA activity during the G 1 /S transition, as suggested previously 17,38 . In support of this, we also see a very subtle increase in S20 and S21 phosphorylation after G 1 release ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 73%

“…We next sought to identify if the increase of higher phosphorylated isoforms is triggered solely by the periodically increasing Cdk1 activity 16 , 19 or whether, PKA phosphorylation increases additionally, as PKA activity has been suggested to increase at the G 1 /S transition 17 , 38 . The Nth1 ∆PKA/S66 revealed no phosphorylation in G 1 -arrested cells, showing that the bands which are present in G 1 are only the four known PKA sites.…”

Section: Resultsmentioning

confidence: 99%

Regulation of trehalase activity by multi-site phosphorylation and 14-3-3 interaction

Dengler

Örd

Schwab

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Protein phosphorylation enables a rapid adjustment of cellular activities to diverse intracellular and environmental stimuli. Many phosphoproteins are targeted on more than one site, which allows the integration of multiple signals and the implementation of complex responses. However, the hierarchy and interplay between multiple phospho-sites are often unknown. Here, we study multi‐site phosphorylation using the yeast trehalase Nth1 and its activator, the 14-3-3 protein Bmh1, as a model. Nth1 is known to be phosphorylated by the metabolic kinase PKA on four serine residues and by the cell cycle kinase CDK on one residue. However, how these five phospho-sites adjust Nth1 activity remains unclear. Using a novel reporter construct, we investigated the contribution of the individual sites for the regulation of the trehalase and its 14-3-3 interactor. In contrast to the constitutively phosphorylated S20 and S83, the weaker sites S21 and S60 are only phosphorylated by increased PKA activity. For binding Bmh1, S83 functions as the high‐affinity “gatekeeper” site, but successful binding of the Bmh1 dimer and thus Nth1 activation requires S60 as a secondary site. Under nutrient-poor conditions with low PKA activity, S60 is not efficiently phosphorylated and the cell cycle dependent phosphorylation of S66 by Cdk1 contributes to Nth1 activity, likely by providing an alternative Bmh1 binding site. Additionally, the PKA sites S20 and S21 modulate the dephosphorylation of Nth1 on downstream Bmh1 sites. In summary, our results expand our molecular understanding of Nth1 regulation and provide a new aspect of the interaction of 14-3-3 proteins with their targets.

show abstract

“…The following eight yeast phosphoproteomic datasets were searched for the presence of phospho-methylarginine peptides: PXD001368, PXD002344, PXD013453, PXD013782, PXD015235, PXD015575, PXD016519, and Swaney et al Data were searched in Proteome Discoverer (v.2.3) using Mascot, as above, with the mass tolerances and modifications listed in Table S1.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Arginine Methylation, Phosphorylation, and Their Co-occurrence in Condensate-Associated Proteins in Saccharomyces cerevisiae

2021

View full text Add to dashboard Cite

The formation of condensates in membraneless organelles is thought to be driven by protein phase separation. Arginine methylation and serine/ threonine phosphorylation are important in the phase separation process; however, these post-translational modifications are often present in intrinsically disordered regions that are difficult to analyze with standard proteomic techniques. To understand their presence and co-occurrence in condensate-associated proteins, here, we use a multiprotease and multi-tandem mass spectrometry (MS/MS) fragmentation approach, coupled with heavy methyl stable isotope labeling of amino acids in cell culture (SILAC) and phospho-or methyl-peptide enrichment. For Saccharomyces cerevisiae, we report a 50% increase in the known arginine methylproteome, involving 15 proteins that are all condensate-associated. Importantly, some of these proteins have arginine methylation on all predicted sitesproviding evidence that this modification can be pervasive. We explored whether arginine-methylated, condensate-associated proteins are also phosphorylated and found 12 such proteins to carry phosphorylated serine or threonine. In Npl3, Ded1, and Sbp1, single peptides were found to carry both modifications, indicating a co-occurrence in close proximity and on the same protein molecule. These co-modifications occur in regions of disorder, whereas arginine methylation is typically on regions of disorder that are also basic. For phosphorylation, its association with charged regions of condensate-associated proteins was less consistent, although some regions with multisite phosphorylation sites were strongly acidic. We conclude that arginine-methylated proteins associated with condensates are typically also modified with protein phosphorylation.

show abstract

Multiple Layers of Phospho-Regulation Coordinate Metabolism and the Cell Cycle in Budding Yeast

Cited by 27 publications

References 77 publications

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

Regulation of trehalase activity by multi-site phosphorylation and 14-3-3 interaction

Discovery of Arginine Methylation, Phosphorylation, and Their Co-occurrence in Condensate-Associated Proteins in Saccharomyces cerevisiae

Contact Info

Product

Resources

About