scholarly journals A CTDNEP1-lipin 1-mTOR regulatory network restricts ER membrane biogenesis to enable chromosome motions necessary for mitotic fidelity

2021 ◽  
Author(s):  
Holly Merta ◽  
Jake W. Carrasquillo Rodríguez ◽  
Maya I. Anjur-Dietrich ◽  
Mitchell E. Granade ◽  
Tevis Vitale ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Mitotic Chromosome ◽  
Lipid Synthesis ◽  
Membrane Biogenesis ◽  
Mitotic Progression ◽  
Potential Source ◽  
Spindle Disassembly ◽  
Lipin 1 ◽  
Chromosome Movements ◽  
Er Membrane

SummaryThe endoplasmic reticulum (ER) dramatically restructures in open mitosis to become excluded from the mitotic spindle; however, the significance of ER reorganization to mitotic progression is not known. Here, we demonstrate that limiting ER membrane biogenesis enables mitotic chromosome movements necessary for chromosome biorientation and prevention of micronuclei formation. Aberrantly expanded ER membranes increase the effective viscosity of the mitotic cytoplasm to physically restrict chromosome dynamics – slowed chromosome motions impede correction of mitotic errors induced by transient spindle disassembly, leading to severe micronucleation. We define the mechanistic link between regulation of ER membrane biogenesis and mitotic fidelity by demonstrating that a CTDNEP1-lipin 1-mTOR regulatory network limits ER lipid synthesis to prevent chromosome missegregation. Together, this work shows that ER membranes reorganize in mitosis to enable chromosome movements necessary for mitotic error correction and reveal dysregulated lipid metabolism as a potential source of aneuploidy in cancer cells.

A CTDNEP 1-Lipin 1-mTOR Regulatory Network Restricts ER Membrane Biogenesis to Enable Chromosome Motions Necessary for Mitotic Fidelity

2021 ◽  
Author(s):  
Holly Merta ◽  
Jake W. Carrasquillo Rodriguez ◽  
Maya I. Anjur-Dietrich ◽  
Mitchell E. Granade ◽  
Tevis Vitale ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Membrane Biogenesis ◽  
Lipin 1 ◽  
Er Membrane

scholarly journals Control of endoplasmic reticulum membrane biogenesis by regulators of lipid metabolism

2020 ◽  
Author(s):  
Peter W. Bircham ◽  
Dimitrios Papagiannidis ◽  
Christian Lüchtenborg ◽  
Giulia Ruffini ◽  
Britta Brügger ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Metabolism ◽  
Transcriptional Control ◽  
Transmembrane Protein ◽  
Lipid Synthesis ◽  
Endoplasmic Reticulum Membrane ◽  
Membrane Biogenesis ◽  
Storage Lipids ◽  
The Unfolded Protein Response ◽  
Er Membrane

ABSTRACTCells dynamically adapt organelle size to current physiological demand. Organelle growth and proliferation require membrane biogenesis and need to be coordinated with lipid metabolism. The endoplasmic reticulum (ER) can undergo massive expansion but the mechanisms that govern ER membrane biogenesis are unclear. Here, we genetically screen for factors mediating ER expansion in budding yeast and identify lipid synthesis enzymes and the ER transmembrane protein Ice2 as strong hits. Ice2 inhibits the conserved phosphatidic acid phosphatase Pah1 by opposing the activity of the Nem1-Spo7 complex. This regulation counteracts the production of storage lipids and directs lipid metabolism towards membrane biogenesis. Furthermore, Ice2 acts in concert with the transcriptional control of lipid synthesis enzymes and cooperates with the unfolded protein response to maintain ER homeostasis. These findings establish the regulation of the lipin ortholog Pah1 as a key determinant of ER membrane biogenesis.

scholarly journals Toxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sheena Dass ◽  
Serena Shunmugam ◽  
Laurence Berry ◽  
Christophe-Sebastien Arnold ◽  
Nicholas J. Katris ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Phosphatidic Acid ◽  
De Novo ◽  
Lipid Synthesis ◽  
Parasite Development ◽  
Membrane Biogenesis ◽  
Membrane Phospholipids ◽  
Phosphatidic Acid Phosphatase ◽  
Intracellular Parasites ◽  
Parasite Survival

AbstractApicomplexa are obligate intracellular parasites responsible for major human diseases. Their intracellular survival relies on intense lipid synthesis, which fuels membrane biogenesis. Parasite lipids are generated as an essential combination of fatty acids scavenged from the host and de novo synthesized within the parasite apicoplast. The molecular and metabolic mechanisms allowing regulation and channeling of these fatty acid fluxes for intracellular parasite survival are currently unknown. Here, we identify an essential phosphatidic acid phosphatase in Toxoplasma gondii, TgLIPIN, as the central metabolic nexus responsible for controlled lipid synthesis sustaining parasite development. Lipidomics reveal that TgLIPIN controls the synthesis of diacylglycerol and levels of phosphatidic acid that regulates the fine balance of lipids between storage and membrane biogenesis. Using fluxomic approaches, we uncover the first parasite host-scavenged lipidome and show that TgLIPIN prevents parasite death by ‘lipotoxicity’ through effective channeling of host-scavenged fatty acids to storage triacylglycerols and membrane phospholipids.

scholarly journals Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

2014 ◽  
Vol 193 (9) ◽  
pp. 4614-4622 ◽  
Author(s):  
Clara Meana ◽  
Lucía Peña ◽  
Gema Lordén ◽  
Esperanza Esquinas ◽  
Carlos Guijas ◽  
...  
Keyword(s):  
Lipid Synthesis ◽  
Proinflammatory Responses ◽  
Lipin 1

Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation

2021 ◽  
Author(s):  
Holly Merta ◽  
Jake W. Carrasquillo Rodríguez ◽  
Maya I. Anjur-Dietrich ◽  
Tevis Vitale ◽  
Mitchell E. Granade ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Membrane Biogenesis ◽  
Chromosome Missegregation ◽  
Cycle Regulation ◽  
Er Membrane

Correlation analysis of the transcriptome and metabolome reveals the regulatory network for lipid synthesis in developing Brassica napus embryos

2018 ◽  
Vol 99 (1-2) ◽  
pp. 31-44 ◽  
Author(s):  
Helin Tan ◽  
Jiahuan Zhang ◽  
Xiao Qi ◽  
Xiaoli Shi ◽  
Jianguo Zhou ◽  
...  
Keyword(s):  
Brassica Napus ◽  
Correlation Analysis ◽  
Regulatory Network ◽  
Lipid Synthesis

scholarly journals A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pooja Sharma ◽  
Robert Mahen ◽  
Maxim Rossmann ◽  
Jamie E. Stokes ◽  
Bryn Hardwick ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
Substrate Recognition ◽  
Genome Integrity ◽  
Mitotic Progression ◽  
New Approach ◽  
Molecule Inhibitor ◽  
Evolutionarily Conserved ◽  
Essential Function ◽  
Carboxyl Terminal

Abstract The human polo-like kinase PLK1 coordinates mitotic chromosome segregation by phosphorylating multiple chromatin- and kinetochore-binding proteins. How PLK1 activity is directed to specific substrates via phosphopeptide recognition by its carboxyl-terminal polo-box domain (PBD) is poorly understood. Here, we combine molecular, structural and chemical biology to identify a determinant for PLK1 substrate recognition that is essential for proper chromosome segregation. We show that mutations ablating an evolutionarily conserved, Tyr-lined pocket in human PLK1 PBD trigger cellular anomalies in mitotic progression and timing. Tyr pocket mutations selectively impair PLK1 binding to the kinetochore phosphoprotein substrate PBIP1, but not to the centrosomal substrate NEDD1. Through a structure-guided approach, we develop a small-molecule inhibitor, Polotyrin, which occupies the Tyr pocket. Polotyrin recapitulates the mitotic defects caused by mutations in the Tyr pocket, further evidencing its essential function, and exemplifying a new approach for selective PLK1 inhibition. Thus, our findings support a model wherein substrate discrimination via the Tyr pocket in the human PLK1 PBD regulates mitotic chromosome segregation to preserve genome integrity.

scholarly journals UPR-Mediated Membrane Biogenesis in B Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Joseph W. Brewer ◽  
Suzanne Jackowski
Keyword(s):  
B Cells ◽  
Lipid Synthesis ◽  
Protein Translation ◽  
Secretory Proteins ◽  
Membrane Biogenesis ◽  
Unfolded Protein ◽  
Client Proteins ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact

The unfolded protein response (UPR) can coordinate the regulation of gene transcription and protein translation to balance the load of client proteins with the protein folding and degradative capacities of the ER. Increasing evidence also implicates the UPR in the regulation of lipid synthesis and membrane biogenesis. The differentiation of B lymphocytes into antibody-secreting cells is marked by significant expansion of the ER, the site for antibody synthesis and assembly. In activated B cells, the demand for membrane protein and lipid components leads to activation of the UPR transcriptional activator XBP1(S) which, in turn, initiates a cascade of biochemical events that enhance supplies of phospholipid precursors and build machinery for the synthesis, maturation, and transport of secretory proteins. The alterations in lipid metabolism that occur during this developmental transition and the impact of membrane phospholipid restriction on B cell secretory characteristics are discussed in this paper.

scholarly journals Changes in lipid synthesis in rat liver during development

1967 ◽  
Vol 102 (3) ◽  
pp. 952-958 ◽  
Author(s):  
F. J. Ballard ◽  
R. W. Hanson
Keyword(s):  
Rat Liver ◽  
Lipid Synthesis ◽  
Adult Liver ◽  
Atp Citrate Lyase ◽  
Adult Rat ◽  
Potential Source ◽  
Liver Slices ◽  
Citrate Lyase ◽  
Glucose Incorporation ◽  
Cleavage Enzyme

1. Lipogenesis, as measured by the incorporation of (14)C-labelled glucose or acetate into fatty acids in liver slices, is high in foetal and adult rat liver but is low in the liver of the suckling rat, especially with glucose as substrate. 2. The rate of synthesis of non-saponifiable lipids from glucose is about 15 times as great in the liver of the 18-day foetus as in adult liver. Activity in the newborn is negligible. 3. Glucose incorporation into fat is strongly concentration-dependent in liver slices from the adult and 2-week-old rat, but less markedly so in liver slices from the foetus. 4. Changes in the activity of hepatic citrate-cleavage enzyme (ATP-citrate lyase) occur in parallel with the changes in the extent of fatty acid formation, supporting the participation of this enzyme in lipogenesis. However, NADP-malate dehydrogenase, a potential source of reduced nucleotide coenzyme for lipogenesis in the adult, could not be detected in foetal rat liver.

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