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      Lysine acetyltransferase NuA4 and acetyl-CoA regulate glucose-deprived stress granule formation in Saccharomyces cerevisiae

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          Abstract

          Eukaryotic cells form stress granules under a variety of stresses, however the signaling pathways regulating their formation remain largely unknown. We have determined that the Saccharomyces cerevisiae lysine acetyltransferase complex NuA4 is required for stress granule formation upon glucose deprivation but not heat stress. Further, the Tip60 complex, the human homolog of the NuA4 complex, is required for stress granule formation in cancer cell lines. Surprisingly, the impact of NuA4 on glucose-deprived stress granule formation is partially mediated through regulation of acetyl-CoA levels, which are elevated in NuA4 mutants. While elevated acetyl-CoA levels suppress the formation of glucose-deprived stress granules, decreased acetyl-CoA levels enhance stress granule formation upon glucose deprivation. Further our work suggests that NuA4 regulates acetyl-CoA levels through the Acetyl-CoA carboxylase Acc1. Altogether this work establishes both NuA4 and the metabolite acetyl-CoA as critical signaling pathways regulating the formation of glucose-deprived stress granules.

          Author summary

          In response to environmental stress, such as nutrient limitations or toxic chemicals, cells must quickly counteract these threats in order to survive. One way cells fight environmental challenges is through the formation of stress granules, which are aggregates of proteins and mRNA within the cytoplasm. Though their formation is essential for survival under multiple conditions, when stress granules are inappropriately formed they become causative for diseases such as amyotrophic lateral sclerosis and fragile X syndrome. Further stress granules contribute to chemotherapy resistance of cancer cells by promoting survival. Therefore it is critical to understand how stress granules are formed and disassembled. Here using the budding yeast Saccharomyces cerevisiae we determine that an enzyme called NuA4 is contributing to stress granule formation upon glucose deprivation. Why is this important? We determine that Tip60, the equivalent of NuA4 in mammalian cells, is also regulating stress granule formation in cancer cells. As there is a growing number of drugs that target this class of enzyme, there is the possibility that these drugs may reduce stress granule formation offering a novel therapeutic approach to treat numerous diseases.

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          Most cited references65

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          Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae.

          An important recent advance in the functional analysis of Saccharomyces cerevisiae genes is the development of the one-step PCR-mediated technique for deletion and modification of chromosomal genes. This method allows very rapid gene manipulations without requiring plasmid clones of the gene of interest. We describe here a new set of plasmids that serve as templates for the PCR synthesis of fragments that allow a variety of gene modifications. Using as selectable marker the S. cerevisiae TRP1 gene or modules containing the heterologous Schizosaccharomyces pombe his5+ or Escherichia coli kan(r) gene, these plasmids allow gene deletion, gene overexpression (using the regulatable GAL1 promoter), C- or N-terminal protein tagging [with GFP(S65T), GST, or the 3HA or 13Myc epitope], and partial N- or C-terminal deletions (with or without concomitant protein tagging). Because of the modular nature of the plasmids, they allow efficient and economical use of a small number of PCR primers for a wide variety of gene manipulations. Thus, these plasmids should further facilitate the rapid analysis of gene function in S. cerevisiae.
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            Acetyl-CoA and the Regulation of Metabolism: Mechanisms and Consequences

            Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Emerging evidence reveals that cells monitor the levels of acetyl-CoA as a key indicator of their metabolic state, through distinctive protein acetylation modifications dependent on this metabolite. We offer the following conceptual model for understanding the role of this sentinel metabolite in metabolic regulation. High nucleocytosolic acetyl-CoA amounts are a signature of a “growth” or “fed” state and promote its utilization for lipid synthesis and histone acetylation. In contrast, under “survival” or “fasted” states, acetyl-CoA is preferentially directed into the mitochondria to promote mitochondrial-dependent activities such as the synthesis of ATP and ketone bodies. Fluctuations in acetyl-CoA within these subcellular compartments enable the substrate-level regulation of acetylation modifications, but also necessitates the function of sirtuin deacetylases to catalyze removal of spontaneous modifications that might be unintended. Thus, understanding the sources, fates, and consequences of acetyl-CoA as a carrier of two-carbon units has started to reveal its underappreciated but profound influence on the regulation of numerous life processes.
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              RNA granules: post-transcriptional and epigenetic modulators of gene expression.

              The composition of cytoplasmic messenger ribonucleoproteins (mRNPs) is determined by their nuclear and cytoplasmic histories and reflects past functions and future fates. The protein components of selected mRNP complexes promote their assembly into microscopically visible cytoplasmic RNA granules, including stress granules, processing bodies and germ cell (or polar) granules. We propose that RNA granules can be both a cause and a consequence of altered mRNA translation, decay or editing. In this capacity, RNA granules serve as key modulators of post-transcriptional and epigenetic gene expression.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                23 February 2017
                February 2017
                : 13
                : 2
                : e1006626
                Affiliations
                [1 ]Ottawa Institute of Systems Biology, uOttawa, Ottawa, Ontario, Canada
                [2 ]Department of Biochemistry, Microbiology and Immunology, uOttawa, Ottawa, Ontario, Canada
                [3 ]Department of Cellular and Molecular Medicine, uOttawa, Ottawa, Ontario, Canada
                University of Toronto, CANADA
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: KB MR JC SH.

                • Formal analysis: MR SH AM TTP.

                • Funding acquisition: KB JC MDF.

                • Investigation: MR SH JT AM TTP.

                • Methodology: JT MR SH AM TTP MDF.

                • Project administration: KB.

                • Supervision: KB JC MDF.

                • Validation: MR SH.

                • Visualization: SH KB AM.

                • Writing – original draft: MR KB.

                • Writing – review & editing: MR KB SH JC AM.

                ‡ These authors share first authorship on this work.

                Author information
                http://orcid.org/0000-0001-8469-0763
                http://orcid.org/0000-0002-2745-2117
                http://orcid.org/0000-0001-9739-1009
                http://orcid.org/0000-0002-7312-195X
                Article
                PGENETICS-D-16-02103
                10.1371/journal.pgen.1006626
                5344529
                28231279
                ca799722-9129-4667-83c0-8f7852b518db
                © 2017 Rollins et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 September 2016
                : 9 February 2017
                Page count
                Figures: 9, Tables: 0, Pages: 27
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000033, Institute of Musculoskeletal Health and Arthritis;
                Award ID: MOP-123381
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000027, Institute of Cancer Research;
                Award ID: MOP-142403
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;
                Award ID: RGPIN-326770
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: OCN143065
                Award Recipient :
                This work was supported by grants from the Natural Sciences and Engineering Research Council (NSERC) of Canada ( http://www.nserc-crsng.gc.ca/index_eng.asp; RGPIN-326770) to KB; Canadian Institutes of Health Research ( http://www.cihr-irsc.gc.ca/e/193.html; MOP-142403) to KB, CIHR (MOP-123381) to JC and CIHR (PJT-148634) to MDF. MR was supported by a NSERC Canadian Graduate Scholarship, JT was supported by an Ontario Government Queen Elizabeth II Graduate Scholarships in Science & Technology ( https://www.sgs.utoronto.ca/currentstudents/Pages/Queen-Elizabeth-II-Graduate-Scholarships.aspx). KB was the recipient of a Canada Research Chair (CRC, http://www.chairs-chaires.gc.ca/home-accueil-eng.aspx) (Tier II) in Functional and Chemical Genomics and JC was the recipient of a CRC (Tier II) in RNA Metabolism. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Chemical Reactions
                Acetylation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Acetylation
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Carbohydrate Metabolism
                Glucose Metabolism
                Research and Analysis Methods
                Experimental Organism Systems
                Model Organisms
                Saccharomyces Cerevisiae
                Research and Analysis Methods
                Model Organisms
                Saccharomyces Cerevisiae
                Biology and Life Sciences
                Organisms
                Fungi
                Yeast
                Saccharomyces
                Saccharomyces Cerevisiae
                Research and Analysis Methods
                Experimental Organism Systems
                Yeast and Fungal Models
                Saccharomyces Cerevisiae
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Glucose Signaling
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Histones
                Biology and Life Sciences
                Organisms
                Fungi
                Yeast
                Biology and Life Sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Mammals
                Cats
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-03-09
                All relevant data are within the paper and its Supporting Information files.

                Genetics
                Genetics

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