Regulation of phospholipid synthesis in yeast

Carman, George M.; Han, Gil‐Soo

doi:10.1194/jlr.r800043-jlr200

Cited by 102 publications

(112 citation statements)

References 53 publications

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“…When inositol levels are low, Scs2 sequesters the transcriptional repressor Opi1 from UAS INO promoter sites (Fig. 7A) (5). In the absence of Scs2, Opi1 remains constitutively bound to UAS INO -containing promoters, thereby inhibiting INO1 transcription and ultimately blocking de novo production of inositol.…”

Section: Resultsmentioning

confidence: 99%

Desumoylation of the Endoplasmic Reticulum Membrane VAP Family Protein Scs2 by Ulp1 and SUMO Regulation of the Inositol Synthesis Pathway

Felberbaum

Wilson

Cheng

et al. 2012

Molecular and Cellular Biology

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Posttranslational protein modification by the ubiquitin-like SUMO protein is critical to eukaryotic cell regulation, but much remains unknown regarding its operation and substrates. Here we report that specific mutations in the Saccharomyces cerevisiae Ulp1 SUMO protease, including its coiled-coil (CC) domain, lead to the accumulation of distinct sumoylated proteins in vivo. A prominent ϳ50-kDa sumoylated protein accumulates in a Ulp1 CC mutant. The protein was identified as Scs2, an endoplasmic reticulum (ER) membrane protein that regulates phosphatidylinositol synthesis and lipid trafficking. Mutation of lysine 180 of Scs2 abolishes its sumoylation. Notably, impairment of either cellular sumoylation or cellular desumoylation mechanisms inhibits cell growth in the absence of inositol and exacerbates the inositol auxotrophy caused by deletion of SCS2. Mutants lacking the Ulp2 SUMO protease are the most severely affected, and this defect was traced to the mutants' impaired ability to induce transcription of INO1, which encodes the rate-limiting enzyme of inositol biosynthesis. Conversely, inositol starvation induces a striking change in the profiles of total cellular SUMO conjugates. These results provide the first evidence of cross-regulation between the SUMO and inositol pathways, including the sumoylation of an ER membrane protein central to phospholipid synthesis and phosphoinositide signaling. The SUMO (small ubiquitin-related modifier) proteins are a family of protein modifiers conserved from the yeast Saccharomyces cerevisiae to humans. Modification of a protein by SUMO (sumoylation) has a variety of outcomes, including alterations of its localization, stability, or interaction with other molecules (18). Increasingly, SUMO is being identified as a key coordinator of protein interaction networks, and disruption to sumoylation has been linked to a variety of disorders, including many cancers and neurodegenerative diseases (25, 41).The yeast S. cerevisiae expresses a single SUMO protein called Smt3. Smt3 is synthesized as an inactive precursor; the three C-terminal residues are removed to yield mature Smt3, which terminates with a pair of Gly residues. Following precursor cleavage, Smt3 enters an enzymatic cascade involving a series of enzymes designated E1, E2, and E3. The heterodimeric E1-activating enzyme Uba2-Aos1 first forms a high-energy thioester bond with the C terminus of Smt3 (22). Activated Smt3 is then transferred to the active-site cysteine of the E2 enzyme Ubc9 (20), from which it is then conjugated to a lysine side chain in a substrate (21). Smt3-substrate conjugation is usually assisted by one of several E3 protein ligases (21, 50). Additional Smt3 proteins can be appended to previously conjugated Smt3 molecules, generating a polySUMO chain.Sumoylation is reversible, and substrates can be desumoylated by specific proteases, termed ubiquitin-like protein-specific proteases (ULPs) (10). S. cerevisiae has two SUMO proteases, Ulp1 and Ulp2, which cleave Smt3 from distinct sets of substrates (29,31...

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Section: Resultsmentioning

confidence: 99%

Desumoylation of the Endoplasmic Reticulum Membrane VAP Family Protein Scs2 by Ulp1 and SUMO Regulation of the Inositol Synthesis Pathway

Felberbaum

Wilson

Cheng

et al. 2012

Molecular and Cellular Biology

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“…The INO1 gene, encoding inositol-3-phosphate synthase, and other genes involved in lipid metabolism are repressed by the Opi1p repressor in response to the presence of exogenous inositol (5)(6)(7)(8)(9)(10). However, the majority of the genes that are regulated in response to inositol availability in wild type cells are not involved in phospholipid metabolism and are not under the control of the Opi1p repressor (1,2).…”

mentioning

confidence: 96%

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Lee¹,

Gaspar²,

Aregullin

et al. 2013

Journal of Biological Chemistry

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Background: Inhibition of complex sphingolipid synthesis by inositol starvation activates the PKC-MAPK signaling pathway. Results: Sir2p-dependent telomeric silencing is activated by interrupting sphingolipid synthesis and requires the MAPK, Slt2p. Conclusion: Telomeric silencing is regulated by PKC-MAPK signaling in response to interruption of sphingolipid synthesis. Significance: Sphingolipid metabolism plays an important role in regulating silencing and chronological life span.

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“…The main alternative pathway for the synthesis of PE is the decarboxylation of PS by a PS decarboxylase (88). This pathway is actually the sole route for PE biosynthesis in E. coli (7, 88, 89 and references therein) and the major one in S. cerevisiae, although in yeast the Kennedy pathway is also active (52,53,88). In mammalian cells, the relative contributions of these pathways to PE formation is cell type dependent, with PS decarboxylation prevailing in BHK21 and CHO cells and the Kennedy pathway prevailing in most mammalian tissues [hamster heart, rat heart, kidney and liver, cultured glioma cells (2, 7, 88, 89 and references therein)].…”

Section: Alternative Phosphatidylethanolamine Synthesismentioning

confidence: 99%

“…In yeast, CK activity can be regulated in multiple ways: at a transcriptional level, together with other genes in lipid biosynthesis, including EK, and via phosphorylation mediated by protein kinases A and C (52). Transcriptional regulation of the yeast EK gene, and thus the flux through the ethanolamine branch of the Kennedy pathway leading to PE formation, has been shown to be dose dependent upon inositol and/or zinc (53).…”

Section: The Choline and Ethanolamine Kinasesmentioning

confidence: 99%

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

2010

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SummaryThe glycerophospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) account for greater than 50% of the total phospholipid species in eukaryotic membranes and thus play major roles in the structure and function of those membranes. In most eukaryotic cells, PC and PE are synthesized by an aminoalcoholphosphotransferase reaction, which uses sn-1,2-diradylglycerol and either CDP-choline or CDP-ethanolamine, respectively. This is the last step in a biosynthetic pathway known as the Kennedy pathway, so named after Eugene Kennedy who elucidated it over 50 years ago. This review will cover various aspects of the Kennedy pathway including: each of the biosynthetic steps, the functions and roles of the phospholipid products PC and PE, and how the Kennedy pathway has the potential of being a chemotherapeutic target against cancer and various infectious diseases. IUBMBIUBMB Life, 62(6): [414][415][416][417][418][419][420][421][422][423][424][425][426][427][428] 2010

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Regulation of phospholipid synthesis in yeast

Cited by 102 publications

References 53 publications

Desumoylation of the Endoplasmic Reticulum Membrane VAP Family Protein Scs2 by Ulp1 and SUMO Regulation of the Inositol Synthesis Pathway

Desumoylation of the Endoplasmic Reticulum Membrane VAP Family Protein Scs2 by Ulp1 and SUMO Regulation of the Inositol Synthesis Pathway

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

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