Publications by authors named "Symeon Siniossoglou"

32 Publications

An Erg11 lanosterol 14-α-demethylase-Arv1 complex is required for Candida albicans virulence.

PLoS One 2020 17;15(7):e0235746. Epub 2020 Jul 17.

Institute of Metabolic Disorders, Genesis Biotechnology Group, Hamilton, New Jersey, United States of America.

Azole resistant fungal infections remain a health problem for the immune compromised. Current therapies are limited due to rises in new resistance mechanisms. Therefore, it is important to identify new drug targets for drug discovery and novel therapeutics. Arv1 (are1 are2 required for viability 1) function is highly conserved between multiple pathogenic fungal species. Candida albicans (C. albicans) cells lacking CaArv1 are azole hypersusceptible and lack virulence. Saccharomyces cerevisiae (S. cerevisiae) Scarv1 cells are also azole hypersusceptible, a phenotype reversed by expression of CaArv1, indicating conservation in the molecular mechanism for azole susceptibility. To define the relationship between Arv1 function and azole susceptibility, we undertook a structure/function analysis of ScArv1. We identified several conserved amino acids within the ScArv1 homology domain (ScAhd) required for maintaining normal azole susceptibility. Erg11 lanosterol 14-α-demethylase is the rate-limiting enzyme in sterol biosynthesis and is the direct target of azole antifungals, so we used our ScArv1 mutants in order to explore the relationship between ScArv1 and ScErg11. Specific ScArv1 mutants ectopically expressed from a low copy plasmid were unable to restore normal azole susceptibility to Scarv1 cells and had reduced Erg11 protein levels. Erg11 protein stability depended on its ability to form a heterodimeric complex with Arv1. Complex formation was required for maintaining normal azole susceptibility. Scarv1 cells expressing orthologous CaArv1 mutants also had reduced CaErg11 levels, were unable to form a CaArv1-CaErg11 complex, and were azole hypersusceptible. Scarv1 cells expressing CaArv1 mutants unable to interact with CaErg11 could not sustain proper levels of the azole resistant CaErg11Y132F F145L protein. Caarv1/Caarv1 cells expressing CaArv1 mutants unable to interact with CaErg11 were found to lack virulence using a disseminated candidiasis mouse model. Expressing CaErg11Y132F F145L did not reverse the lack of virulence. We hypothesize that the role of Arv1 in Erg11-dependent azole resistance is to stabilize Erg11 protein level. Arv1 inhibition may represent an avenue for treating azole resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235746PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367482PMC
September 2020

New kid on the block: lipid droplets in the nucleus.

FEBS J 2020 Nov 17;287(22):4838-4843. Epub 2020 Apr 17.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

The regulation of lipid homeostasis is essential for normal cell physiology, and its disruption can lead to disease. Lipid droplets (LDs) are ubiquitous organelles dedicated to storing nonpolar lipids that are used for metabolic energy production or membrane biogenesis. LDs normally emerge from, and associate with, the endoplasmic reticulum and interact with other cytoplasmic organelles to deliver the stored lipids. Recently, LDs were found to reside also at the inner side of the nuclear envelope and inside the nucleus in yeast and mammalian cells. This unexpected finding raises fundamental questions about the nature of the inner nuclear membrane, its connection with the endoplasmic reticulum and the pathways of LD formation. In this viewpoint, we will highlight recent developments relating to these questions and discuss possible roles of LDs in nuclear physiology.
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http://dx.doi.org/10.1111/febs.15307DOI Listing
November 2020

Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration.

Neuron 2020 01 27;105(2):276-292.e5. Epub 2019 Nov 27.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China; Center of Systems Biology and Human Health, School of Science and Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China. Electronic address:

How adult neurons coordinate lipid metabolism to regenerate axons remains elusive. We found that depleting neuronal lipin1, a key enzyme controlling the balanced synthesis of glycerolipids through the glycerol phosphate pathway, enhanced axon regeneration after optic nerve injury. Axotomy elevated lipin1 in retinal ganglion cells, which contributed to regeneration failure in the CNS by favorably producing triglyceride (TG) storage lipids rather than phospholipid (PL) membrane lipids in neurons. Regrowth induced by lipin1 depletion required TG hydrolysis and PL synthesis. Decreasing TG synthesis by deleting neuronal diglyceride acyltransferases (DGATs) and enhancing PL synthesis through the Kennedy pathway promoted axon regeneration. In addition, peripheral neurons adopted this mechanism for their spontaneous axon regeneration. Our study reveals a critical role of lipin1 and DGATs as intrinsic regulators of glycerolipid metabolism in neurons and indicates that directing neuronal lipid synthesis away from TG synthesis and toward PL synthesis may promote axon regeneration.
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http://dx.doi.org/10.1016/j.neuron.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975164PMC
January 2020

Compartmentalized Synthesis of Triacylglycerol at the Inner Nuclear Membrane Regulates Nuclear Organization.

Dev Cell 2019 09 15;50(6):755-766.e6. Epub 2019 Aug 15.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address:

Cells dynamically adjust organelle organization in response to growth and environmental cues. This requires regulation of synthesis of phospholipids, the building blocks of organelle membranes, or remodeling of their fatty-acyl (FA) composition. FAs are also the main components of triacyglycerols (TGs), which enable energy storage in lipid droplets. How cells coordinate FA metabolism with organelle biogenesis during cell growth remains unclear. Here, we show that Lro1, an acyltransferase that generates TGs from phospholipid-derived FAs in yeast, relocates from the endoplasmic reticulum to a subdomain of the inner nuclear membrane. Lro1 nuclear targeting is regulated by cell cycle and nutrient starvation signals and is inhibited when the nucleus expands. Lro1 is active at this nuclear subdomain, and its compartmentalization is critical for nuclear integrity. These data suggest that Lro1 nuclear targeting provides a site of TG synthesis, which is coupled with nuclear membrane remodeling.
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http://dx.doi.org/10.1016/j.devcel.2019.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859503PMC
September 2019

PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress.

Dev Cell 2018 05 10;45(4):481-495.e8. Epub 2018 May 10.

Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address:

Cell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate-limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis.
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http://dx.doi.org/10.1016/j.devcel.2018.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971203PMC
May 2018

Function of lipid droplet-organelle interactions in lipid homeostasis.

Biochim Biophys Acta Mol Cell Res 2017 Sep 5;1864(9):1459-1468. Epub 2017 Apr 5.

Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, United Kingdom. Electronic address:

Storage of non-polar lipids in ubiquitous eukaryotic organelles, lipid droplets (LDs), prevents the toxic consequences of unesterified fatty acids and provides a lipid reservoir that can be promptly used to satisfy cellular needs under multiple metabolic and physiological conditions. Tight temporal and spatial control of LD biogenesis and mobilization of neutral lipids is essential for the correct channelling of lipid intermediates to their various cellular destinations and the maintenance of cellular homeostasis. These functions are mediated by multiple interactions between LDs and other intracellular organelles that are required for the delivery of stored lipids. Here we review recent advances in the interactions of LDs with the endoplasmic reticulum (ER), mitochondria and vacuole/lysosome. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
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http://dx.doi.org/10.1016/j.bbamcr.2017.04.001DOI Listing
September 2017

Spatial distribution of lipid droplets during starvation: Implications for lipophagy.

Commun Integr Biol 2016 Jul-Aug;9(4):e1183854. Epub 2016 Jun 24.

Cambridge Institute for Medical Research, University of Cambridge , Cambridge, UK.

Survival during starvation depends largely on metabolic energy, which is stored in the form of neutral lipids in specialized organelles known as lipid droplets. The precursors for the synthesis of neutral lipids are also used for membrane biogenesis, which is required for cell growth and proliferation. Therefore cells must possess mechanisms to preferentially channel lipid precursors toward either membrane synthesis or lipid droplet storage, in response to nutrient status. How this partitioning is spatially regulated within the endoplasmic reticulum (ER) where lipid droplets co-localize, remains poorly understood. We have recently shown that at the onset of starvation lipid droplets concentrate at a perinuclear ER subdomain flanking the nucleus-vacuole junction (NVJ) and that this is crucial for maintaining proper nuclear shape and ER membrane organization. Here we show that disruption of the NVJ does not block the translocation and internalization of lipid droplets into the vacuole for their degradation, which takes place at later stages of starvation. We propose that alternative pathways of lipid droplet translocation from the ER to the vacuole may exist to enable stationary phase-induced lipophagy.
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http://dx.doi.org/10.1080/19420889.2016.1183854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988446PMC
August 2016

Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes.

Diabetologia 2016 09 25;59(9):1985-94. Epub 2016 Jun 25.

Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain.

Aims/hypothesis: In mammals, the evolutionary conserved family of Mg(2+)-dependent phosphatidate phosphatases (PAP1), involved in phospholipid and triacylglycerol synthesis, consists of lipin-1, lipin-2 and lipin-3. While mutations in the murine Lpin1 gene cause lipodystrophy and its knockdown in mouse 3T3-L1 cells impairs adipogenesis, deleterious mutations of human LPIN1 do not affect adipose tissue distribution. However, reduced LPIN1 and PAP1 activity has been described in participants with type 2 diabetes. We aimed to characterise the roles of all lipin family members in human adipose tissue and adipogenesis.

Methods: The expression of the lipin family was analysed in adipose tissue in a cross-sectional study. Moreover, the effects of lipin small interfering RNA (siRNA)-mediated depletion on in vitro human adipogenesis were assessed.

Results: Adipose tissue gene expression of the lipin family is altered in type 2 diabetes. Depletion of every lipin family member in a human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, alters expression levels of adipogenic transcription factors and lipid biosynthesis genes in early stages of differentiation. Lipin-1 knockdown alone causes a 95% depletion of PAP1 activity. Despite the reduced PAP1 activity and alterations in early adipogenesis, lipin-silenced cells differentiate and accumulate neutral lipids. Even combinatorial knockdown of lipins shows mild effects on triacylglycerol accumulation in mature adipocytes.

Conclusions/interpretation: Overall, our data support the hypothesis of alternative pathways for triacylglycerol synthesis in human adipocytes under conditions of repressed lipin expression. We propose that induction of alternative lipid phosphate phosphatases, along with the inhibition of lipid hydrolysis, contributes to the maintenance of triacylglycerol content to near normal levels.
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http://dx.doi.org/10.1007/s00125-016-4018-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969345PMC
September 2016

Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1-3.

J Biol Chem 2016 Mar 7;291(13):6664-78. Epub 2016 Jan 7.

From the University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom,

Perilipins (PLINs) play a key role in energy storage by orchestrating the activity of lipases on the surface of lipid droplets. Failure of this activity results in severe metabolic disease in humans. Unlike all other lipid droplet-associated proteins, PLINs localize almost exclusively to the phospholipid monolayer surrounding the droplet. To understand how they sense and associate with the unique topology of the droplet surface, we studied the localization of human PLINs inSaccharomyces cerevisiae,demonstrating that the targeting mechanism is highly conserved and that 11-mer repeat regions are sufficient for droplet targeting. Mutations designed to disrupt folding of this region into amphipathic helices (AHs) significantly decreased lipid droplet targetingin vivoandin vitro Finally, we demonstrated a substantial increase in the helicity of this region in the presence of detergent micelles, which was prevented by an AH-disrupting missense mutation. We conclude that highly conserved 11-mer repeat regions of PLINs target lipid droplets by folding into AHs on the droplet surface, thus enabling PLINs to regulate the interface between the hydrophobic lipid core and its surrounding hydrophilic environment.
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http://dx.doi.org/10.1074/jbc.M115.691048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807253PMC
March 2016

Lipid partitioning at the nuclear envelope controls membrane biogenesis.

Mol Biol Cell 2015 Oct 12;26(20):3641-57. Epub 2015 Aug 12.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom

Partitioning of lipid precursors between membranes and storage is crucial for cell growth, and its disruption underlies pathologies such as cancer, obesity, and type 2 diabetes. However, the mechanisms and signals that regulate this process are largely unknown. In yeast, lipid precursors are mainly used for phospholipid synthesis in nutrient-rich conditions in order to sustain rapid proliferation but are redirected to triacylglycerol (TAG) stored in lipid droplets during starvation. Here we investigate how cells reprogram lipid metabolism in the endoplasmic reticulum. We show that the conserved phosphatidate (PA) phosphatase Pah1, which generates diacylglycerol from PA, targets a nuclear membrane subdomain that is in contact with growing lipid droplets and mediates TAG synthesis. We find that cytosol acidification activates the master regulator of Pah1, the Nem1-Spo7 complex, thus linking Pah1 activity to cellular metabolic status. In the absence of TAG storage capacity, Pah1 still binds the nuclear membrane, but lipid precursors are redirected toward phospholipids, resulting in nuclear deformation and a proliferation of endoplasmic reticulum membrane. We propose that, in response to growth signals, activation of Pah1 at the nuclear envelope acts as a switch to control the balance between membrane biogenesis and lipid storage.
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http://dx.doi.org/10.1091/mbc.E15-03-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603934PMC
October 2015

Lipid droplet-organelle interactions: emerging roles in lipid metabolism.

Curr Opin Cell Biol 2015 Aug 15;35:91-7. Epub 2015 May 15.

Cambridge Institute for Medical Research, University of Cambridge, CB2 0XY Cambridge, United Kingdom. Electronic address:

Cellular homeostasis depends on the precisely coordinated use of lipids as fuels for energy production, building blocks for membrane biogenesis or chemical signals for intra-cellular and inter-cellular communication. Lipid droplets (LDs) are universally conserved dynamic organelles that can store and mobilize fatty acids and other lipid species for their multiple cellular roles. Increasing evidence suggests that contact zones between LDs and other organelles play important roles in the trafficking of lipids and in the regulation of lipid metabolism. Here we review recent advances regarding the nature and functional relevance of interactions between LDs and other organelles-particularly the endoplasmic reticulum (ER), LDs, mitochondria and vacuoles-that highlight their importance for lipid metabolism.
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http://dx.doi.org/10.1016/j.ceb.2015.04.017DOI Listing
August 2015

CK1δ restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1α/ARNT complex formation.

Cell Signal 2015 Jun 3;27(6):1129-40. Epub 2015 Mar 3.

Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece. Electronic address:

Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1α, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1δ phosphorylates HIF-1α in its N-terminus and reduces its affinity for its heterodimerization partner ARNT. To investigate the importance of this mechanism for cell proliferation under hypoxia, we visually monitored HIF-1α interactions within the cell nucleus using the in situ proximity ligation assay (PLA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1δ-dependent modification of HIF-1α impairs the formation of a chromatin binding HIF-1 complex. This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation. Inhibition of CK1δ increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1α- and lipin-1-dependent manner. These data reveal a novel role for CK1δ in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.
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http://dx.doi.org/10.1016/j.cellsig.2015.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390155PMC
June 2015

Distinct roles of the phosphatidate phosphatases lipin 1 and 2 during adipogenesis and lipid droplet biogenesis in 3T3-L1 cells.

J Biol Chem 2013 Nov 16;288(48):34502-13. Epub 2013 Oct 16.

From the Cambridge Institute for Medical Research, University of Cambridge, CB2 0XY Cambridge, United Kingdom.

Lipins are evolutionarily conserved Mg(2+)-dependent phosphatidate phosphatase (PAP) enzymes with essential roles in lipid biosynthesis. Mammals express three paralogues: lipins 1, 2, and 3. Loss of lipin 1 in mice inhibits adipogenesis at an early stage of differentiation and results in a lipodystrophic phenotype. The role of lipins at later stages of adipogenesis, when cells initiate the formation of lipid droplets, is less well characterized. We found that depletion of lipin 1, after the initiation of differentiation in 3T3-L1 cells but before the loading of lipid droplets with triacylglycerol, results in a reciprocal increase of lipin 2, but not lipin 3. We generated 3T3-L1 cells where total lipin protein and PAP activity levels are down-regulated by the combined depletion of lipins 1 and 2 at day 4 of differentiation. These cells still accumulated triacylglycerol but displayed a striking fragmentation of lipid droplets without significantly affecting their total volume per cell. This was due to the lack of the PAP activity of lipin 1 in adipocytes after day 4 of differentiation, whereas depletion of lipin 2 led to an increase of lipid droplet volume per cell. We propose that in addition to their roles during early adipogenesis, lipins also have a role in lipid droplet biogenesis.
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http://dx.doi.org/10.1074/jbc.M113.488445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843065PMC
November 2013

Transcription factor Reb1p regulates DGK1-encoded diacylglycerol kinase and lipid metabolism in Saccharomyces cerevisiae.

J Biol Chem 2013 Oct 22;288(40):29124-33. Epub 2013 Aug 22.

From the Department of Food Science, Rutgers Center for Lipid Research, and New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, New Jersey 08901 and.

In the yeast Saccharomyces cerevisiae, the DGK1-encoded diacylglycerol kinase catalyzes the CTP-dependent phosphorylation of diacylglycerol to form phosphatidate. This enzyme, in conjunction with PAH1-encoded phosphatidate phosphatase, controls the levels of phosphatidate and diacylglycerol for phospholipid synthesis, membrane growth, and lipid droplet formation. In this work, we showed that a functional level of diacylglycerol kinase is regulated by the Reb1p transcription factor. In the electrophoretic mobility shift assay, purified recombinant Reb1p was shown to specifically bind its consensus recognition sequence (CGGGTAA, -166 to -160) in the DGK1 promoter. Analysis of cells expressing the PDGK1-lacZ reporter gene showed that mutations (GT→TG) in the Reb1p-binding sequence caused an 8.6-fold reduction in β-galactosidase activity. The expression of DGK1(reb1), a DGK1 allele containing the Reb1p-binding site mutation, was greatly lower than that of the wild type allele, as indicated by analyses of DGK1 mRNA, Dgk1p, and diacylglycerol kinase activity. In the presence of cerulenin, an inhibitor of de novo fatty acid synthesis, the dgk1Δ mutant expressing DGK1(reb1) exhibited a significant defect in growth as well as in the synthesis of phospholipids from triacylglycerol mobilization. Unlike DGK1, the DGK1(reb1) expressed in the dgk1Δ pah1Δ mutant did not result in the nuclear/endoplasmic reticulum membrane expansion, which occurs in cells lacking phosphatidate phosphatase activity. Taken together, these results indicate that the Reb1p-mediated regulation of diacylglycerol kinase plays a major role in its in vivo functions in lipid metabolism.
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http://dx.doi.org/10.1074/jbc.M113.507392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790011PMC
October 2013

Regulation of lipid droplet and membrane biogenesis by the acidic tail of the phosphatidate phosphatase Pah1p.

Mol Biol Cell 2013 Jul 8;24(13):2124-33. Epub 2013 May 8.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.

Lipins are evolutionarily conserved phosphatidate phosphatases that perform key functions in phospholipid, triglyceride, and membrane biogenesis. Translocation of lipins on membranes requires their dephosphorylation by the Nem1p-Spo7p transmembrane phosphatase complex through a poorly understood mechanism. Here we identify the carboxy-terminal acidic tail of the yeast lipin Pah1p as an important regulator of this step. Deletion or mutations of the tail disrupt binding of Pah1p to the Nem1p-Spo7p complex and Pah1p membrane translocation. Overexpression of Nem1p-Spo7p drives the recruitment of Pah1p in the vicinity of lipid droplets in an acidic tail-dependent manner and induces lipid droplet biogenesis. Genetic analysis shows that the acidic tail is essential for the Nem1p-Spo7p-dependent activation of Pah1p but not for the function of Pah1p itself once it is dephosphorylated. Loss of the tail disrupts nuclear structure, INO1 gene expression, and triglyceride synthesis. Similar acidic sequences are present in the carboxy-terminal ends of all yeast lipin orthologues. We propose that acidic tail-dependent binding and dephosphorylation of Pah1p by the Nem1p-Spo7p complex is an important determinant of its function in lipid and membrane biogenesis.
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http://dx.doi.org/10.1091/mbc.E13-01-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694796PMC
July 2013

Phospholipid metabolism and nuclear function: roles of the lipin family of phosphatidic acid phosphatases.

Biochim Biophys Acta 2013 Mar 29;1831(3):575-81. Epub 2012 Sep 29.

Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, United Kingdom.

Phospholipids play important roles in nuclear function as dynamic building blocks for the biogenesis of the nuclear membrane, as well as signals by which the nucleus communicates with other organelles, and regulate a variety of nuclear events. The mechanisms underlying the nuclear roles of phospholipids remain poorly understood. Lipins represent a family of phosphatidic acid (PA) phosphatases that are conserved from yeasts to humans and perform essential functions in lipid metabolism. Several studies have identified key roles for lipins and their regulators in nuclear envelope organization, gene expression and the maintenance of lipid homeostasis in yeast and metazoans. This review discusses recent advances in understanding the roles of lipins in nuclear structure and function. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
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http://dx.doi.org/10.1016/j.bbalip.2012.09.014DOI Listing
March 2013

Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression.

J Cell Sci 2012 Jul 30;125(Pt 14):3485-93. Epub 2012 Mar 30.

Laboratory of Biochemistry, Medical School, University of Thessaly, BIOPOLIS, Larissa 41110, Greece.

Adaptation to hypoxia involves hypoxia-inducible transcription factors (HIFs) and requires reprogramming of cellular metabolism that is essential during both physiological and pathological processes. In contrast to the established role of HIF-1 in glucose metabolism, the involvement of HIFs and the molecular mechanisms concerning the effects of hypoxia on lipid metabolism are poorly characterized. Here, we report that exposure of human cells to hypoxia causes accumulation of triglycerides and lipid droplets. This is accompanied by induction of lipin 1, a phosphatidate phosphatase isoform that catalyzes the penultimate step in triglyceride biosynthesis, whereas lipin 2 remains unaffected. Hypoxic upregulation of lipin 1 expression involves predominantly HIF-1, which binds to a single distal hypoxia-responsive element in the lipin 1 gene promoter and causes its activation under low oxygen conditions. Accumulation of hypoxic triglycerides or lipid droplets can be blocked by siRNA-mediated silencing of lipin 1 expression or kaempferol-mediated inhibition of HIF-1. We conclude that direct control of lipin 1 transcription by HIF-1 is an important regulatory feature of lipid metabolism and its adaptation to hypoxia.
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http://dx.doi.org/10.1242/jcs.106682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516382PMC
July 2012

The human lipodystrophy protein seipin is an ER membrane adaptor for the adipogenic PA phosphatase lipin 1.

Mol Metab 2012 26;2(1):38-46. Epub 2012 Dec 26.

University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.

Disruption of the gene BSCL2 causes a severe, generalised lipodystrophy, demonstrating the critical role of its protein product, seipin, in human adipose tissue development. Seipin is essential for adipocyte differentiation, whilst the study of seipin in non-adipose cells has suggested a role in lipid droplet formation. However, its precise molecular function remains poorly understood. Here we demonstrate that seipin can inducibly bind lipin 1, a phosphatidic acid (PA) phosphatase important for lipid synthesis and adipogenesis. Knockdown of seipin during early adipogenesis decreases the association of lipin 1 with membranes and increases the accumulation of its substrate PA. Conversely, PA levels are reduced in differentiating cells by overexpression of wild-type seipin but not by expression of a mutated seipin that is unable to bind lipin 1. Together our data identify lipin as the first example of a seipin-interacting protein and reveals a novel molecular function for seipin in developing adipocytes.
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http://dx.doi.org/10.1016/j.molmet.2012.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757660PMC
September 2013

Phosphorylation of phosphatidate phosphatase regulates its membrane association and physiological functions in Saccharomyces cerevisiae: identification of SER(602), THR(723), AND SER(744) as the sites phosphorylated by CDC28 (CDK1)-encoded cyclin-dependent kinase.

J Biol Chem 2011 Jan 16;286(2):1486-98. Epub 2010 Nov 16.

Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA.

The Saccharomyces cerevisiae PAH1-encoded phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol and plays a role in the transcriptional regulation of phospholipid synthesis genes. PAP is phosphorylated at multiple Ser and Thr residues and is dephosphorylated for in vivo function by the Nem1p-Spo7p protein phosphatase complex localized in the nuclear/endoplasmic reticulum membrane. In this work, we characterized seven previously identified phosphorylation sites of PAP that are within the Ser/Thr-Pro motif. When expressed on a low copy plasmid, wild type PAP could not complement the pah1Δ mutant in the absence of the Nem1p-Spo7p complex. However, phosphorylation-deficient PAP (PAP-7A) containing alanine substitutions for the seven phosphorylation sites bypassed the requirement of the phosphatase complex and complemented the pah1Δ nem1Δ mutant phenotypes, such as temperature sensitivity, nuclear/endoplasmic reticulum membrane expansion, decreased triacylglycerol synthesis, and derepression of INO1 expression. Subcellular fractionation coupled with immunoblot analysis showed that PAP-7A was highly enriched in the membrane fraction. In fluorescence spectroscopy analysis, the PAP-7A showed tighter association with phospholipid vesicles than wild type PAP. Using site-directed mutagenesis of PAP, we identified Ser(602), Thr(723), and Ser(744), which belong to the seven phosphorylation sites, as the sites phosphorylated by the CDC28 (CDK1)-encoded cyclin-dependent kinase. Compared with the dephosphorylation mimic of the seven phosphorylation sites, alanine substitution for Ser(602), Thr(723), and/or Ser(744) had a partial effect on circumventing the requirement for the Nem1p-Spo7p complex.
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http://dx.doi.org/10.1074/jbc.M110.155598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020757PMC
January 2011

A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase.

Proc Natl Acad Sci U S A 2010 Oct 27;107(41):17539-44. Epub 2010 Sep 27.

Cambridge Institute for Medical Research, University of Cambridge Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.

Regulation of membrane lipid composition is crucial for many aspects of cell growth and development. Lipins, a novel family of phosphatidate (PA) phosphatases that generate diacylglycerol (DAG) from PA, are emerging as essential regulators of fat metabolism, adipogenesis, and organelle biogenesis. The mechanisms that govern lipin translocation onto membranes are largely unknown. Here we show that recruitment of the yeast lipin (Pah1p) is regulated by PA levels onto the nuclear/endoplasmic reticulum (ER) membrane. Recruitment requires the transmembrane protein phosphatase complex Nem1p-Spo7p. Once dephosphorylated, Pah1p can bind to the nuclear/ER membrane independently of Nem1p-Spo7p via a short amino-terminal amphipathic helix. Dephosphorylation enhances the activity of Pah1p, both in vitro and in vivo, but only in the presence of a functional helix. The helix is required for both phospholipid and triacylglycerol biosynthesis. Our data suggest that dephosphorylation of Pah1p by the Nem1p-Spo7p complex enables the amphipathic helix to anchor Pah1p onto the nuclear/ER membrane allowing the production of DAG for lipid biosynthesis.
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http://dx.doi.org/10.1073/pnas.1007974107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955120PMC
October 2010

Lipins, lipids and nuclear envelope structure.

Traffic 2009 Sep 20;10(9):1181-7. Epub 2009 May 20.

Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK.

The lipid composition of biological membranes is crucial for many aspects of organelle function, including growth, signalling, and transport. Lipins represent a novel family of lipid phosphatases that dephosphorylate phosphatidic acid (PA) to produce diacylglycerol (DAG), and perform key functions in phospholipid and triacylglycerol biosynthesis and gene expression. In addition to its role in lipid biosynthesis, the yeast lipin Pah1p and its regulators are required for the maintenance of a spherical nuclear shape. This review summarizes recent advances in our understanding of the yeast lipin Pah1p and highlights the possible roles of phospholipid metabolism in nuclear membrane biogenesis.
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http://dx.doi.org/10.1111/j.1600-0854.2009.00923.xDOI Listing
September 2009

Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2.

J Biol Chem 2008 Oct 11;283(43):29166-74. Epub 2008 Aug 11.

Cambridge Institute for Medical Research, University of Cambridge, Hills Road, CB2 0XY Cambridge, United Kingdom.

Lipins are the founding members of a novel family of Mg(2+)-dependent phosphatidate phosphatases (PAP1 enzymes) that play key roles in fat metabolism and lipid biosynthesis. Despite their importance, there is still little information on how their activity is regulated. Here we demonstrate that the functions of lipin 1 and 2 are evolutionarily conserved from unicellular eukaryotes to mammals. The two lipins display distinct intracellular localization in HeLa M cells, with a pool of lipin 2 exhibiting a tight membrane association. Small interfering RNA-mediated silencing of lipin 1 leads to a dramatic decrease of the cellular PAP1 activity in HeLa M cells, whereas silencing of lipin 2 leads to an increase of lipin 1 levels and PAP1 activity. Consistent with their distinct functions in HeLa M cells, lipin 1 and 2 exhibit reciprocal patterns of protein expression in differentiating 3T3-L1 adipocytes. Lipin 2 levels increase in lipin 1-depleted 3T3-L1 cells without rescuing the adipogenic defects, whereas depletion of lipin 2 does not inhibit adipogenesis. Finally, we show that the PAP1 activity of both lipins is inhibited by phosphorylation during mitosis, leading to a decrease in the cellular PAP1 activity during cell division. We propose that distinct and non-redundant functions of lipin 1 and 2 regulate lipid production during the cell cycle and adipocyte differentiation.
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http://dx.doi.org/10.1074/jbc.M804278200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570901PMC
October 2008

Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations.

Diabetes 2008 Sep 30;57(9):2527-33. Epub 2008 Jun 30.

Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, U.K.

Objective: Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes.

Research Design And Method: Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3' untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects.

Results: We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects.

Conclusions: Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.
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http://dx.doi.org/10.2337/db08-0422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518506PMC
September 2008

Characterization of the yeast DGK1-encoded CTP-dependent diacylglycerol kinase.

J Biol Chem 2008 Jul 5;283(29):20443-53. Epub 2008 May 5.

Department of Food Science and the Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA.

The Saccharomyces cerevisiae DGK1 gene encodes a diacylglycerol kinase enzyme that catalyzes the formation of phosphatidate from diacylglycerol. Unlike the diacylglycerol kinases from bacteria, plants, and animals, the yeast enzyme utilizes CTP, instead of ATP, as the phosphate donor in the reaction. Dgk1p contains a CTP transferase domain that is present in the SEC59-encoded dolichol kinase and CDS1-encoded CDP-diacylglycerol synthase enzymes. Deletion analysis showed that the CTP transferase domain was sufficient for diacylglycerol kinase activity. Point mutations (R76A, K77A, D177A, and G184A) of conserved residues within the CTP transferase domain caused a loss of diacylglycerol kinase activity. Analysis of DGK1 alleles showed that the in vivo functions of Dgk1p were specifically due to its diacylglycerol kinase activity. The DGK1-encoded enzyme had a pH optimum at 7.0-7.5, required Ca(2+) or Mg(2+) ions for activity, was potently inhibited by N-ethylmaleimide, and was labile at temperatures above 40 degrees C. The enzyme exhibited positive cooperative (Hill number = 2.5) kinetics with respect to diacylglycerol (apparent K(m) = 6.5 mol %) and saturation kinetics with respect to CTP (apparent K(m) = 0.3 mm). dCTP was both a substrate (apparent K(m) = 0.4 mm) and competitive inhibitor (apparent K(i) = 0.4 mm) of the enzyme. Diacylglycerol kinase activity was stimulated by major membrane phospholipids and was inhibited by CDP-diacylglycerol and sphingoid bases.
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http://dx.doi.org/10.1074/jbc.M802866200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2459283PMC
July 2008

An unconventional diacylglycerol kinase that regulates phospholipid synthesis and nuclear membrane growth.

J Biol Chem 2008 Jul 5;283(29):20433-42. Epub 2008 May 5.

Department of Food Science and the Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA.

Changes in nuclear size and shape during the cell cycle or during development require coordinated nuclear membrane remodeling, but the underlying molecular events are largely unknown. We have shown previously that the activity of the conserved phosphatidate phosphatase Pah1p/Smp2p regulates nuclear structure in yeast by controlling phospholipid synthesis and membrane biogenesis at the nuclear envelope. Two screens for novel regulators of phosphatidate led to the identification of DGK1. We show that Dgk1p is a unique diacylglycerol kinase that uses CTP, instead of ATP, to generate phosphatidate. DGK1 counteracts the activity of PAH1 at the nuclear envelope by controlling phosphatidate levels. Overexpression of DGK1 causes the appearance of phosphatidate-enriched membranes around the nucleus and leads to its expansion, without proliferating the cortical endoplasmic reticulum membrane. Mutations that decrease phosphatidate levels decrease nuclear membrane growth in pah1Delta cells. We propose that phosphatidate metabolism is a critical factor determining nuclear structure by regulating nuclear membrane biogenesis.
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http://dx.doi.org/10.1074/jbc.M802903200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2459266PMC
July 2008

The cellular functions of the yeast lipin homolog PAH1p are dependent on its phosphatidate phosphatase activity.

J Biol Chem 2007 Dec 30;282(51):37026-35. Epub 2007 Oct 30.

Department of Food Science and the Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA.

The Saccharomyces cerevisiae PAH1-encoded Mg2+-dependent phosphatidate phosphatase (PAP1, 3-sn-phosphatidate phosphohydrolase, EC 3.1.3.4) catalyzes the dephosphorylation of phosphatidate to yield diacylglycerol and Pi. This enzyme plays a major role in the synthesis of triacylglycerols and phospholipids in S. cerevisiae. PAP1 contains the DXDX(T/V) catalytic motif (DIDGT at residues 398-402) that is shared by the mammalian fat-regulating protein lipin 1 and the superfamily of haloacid dehalogenase-like proteins. The yeast enzyme also contains a conserved glycine residue (Gly80) that is essential for the fat-regulating function of lipin 1 in a mouse model. In this study, we examined the roles of the putative catalytic motif and the conserved glycine for PAP1 activity by a mutational analysis. The PAP1 activities of the D398E and D400E mutant enzymes were reduced by >99.9%, and the activity of the G80R mutant enzyme was reduced by 98%. The mutant PAH1 alleles whose products lacked PAP1 activity were nonfunctional in vivo and failed to complement the pah1Delta mutant phenotypes of temperature sensitivity, respiratory deficiency, nuclear/endoplasmic reticulum membrane expansion, derepression of INO1 expression, and alterations in lipid composition. These results demonstrated that the PAP1 activity of the PAH1 gene product is essential for its roles in lipid metabolism and cell physiology.
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http://dx.doi.org/10.1074/jbc.M705777200DOI Listing
December 2007

Colorimetric determination of pure Mg(2+)-dependent phosphatidate phosphatase activity.

Anal Biochem 2008 Feb 1;373(2):392-4. Epub 2007 Sep 1.

Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, U.S.A.

The malachite green-molybdate reagent was used for a colorimetric assay of pure Mg2(+)-dependent phosphatidate phosphatase activity. This enzyme plays a major role in fat metabolism. Enzyme activity was linear with time and protein concentration, and with the concentration of water-soluble dioctanoyl phosphatidate. The colorimetric assay was used to examine enzyme inhibition by phenylglyoxal, propranolol, and dimethyl sulfoxide. Pure enzyme and a water-soluble phosphatidate substrate were required for the assay, which should be applicable to a well-defined large-scale screen of Mg2(+)-dependent phosphatidate phosphatise inhibitors (or activators).
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http://dx.doi.org/10.1016/j.ab.2007.08.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194655PMC
February 2008

Control of phospholipid synthesis by phosphorylation of the yeast lipin Pah1p/Smp2p Mg2+-dependent phosphatidate phosphatase.

J Biol Chem 2006 Nov 12;281(45):34537-48. Epub 2006 Sep 12.

Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, CB2 2XY Cambridge, United Kingdom.

Phosphorylation of the conserved lipin Pah1p/Smp2p in Saccharomyces cerevisiae was previously shown to control transcription of phospholipid biosynthetic genes and nuclear structure by regulating the amount of membrane present at the nuclear envelope (Santos-Rosa, H., Leung, J., Grimsey, N., Peak-Chew, S., and Siniossoglou, S. (2005) EMBO J. 24, 1931-1941). A recent report identified Pah1p as a Mg2+-dependent phosphatidate (PA) phosphatase that regulates de novo lipid synthesis (Han G.-S., Wu, W. I., and Carman, G. M. (2006) J. Biol. Chem. 281, 9210-9218). In this work we use a combination of mass spectrometry and systematic mutagenesis to identify seven Ser/Thr-Pro motifs within Pah1p that are phosphorylated in vivo. We show that phosphorylation on these sites is required for the efficient transcriptional derepression of key enzymes involved in phospholipid biosynthesis. The phosphorylation-deficient Pah1p exhibits higher PA phosphatase-specific activity than the wild-type Pah1p, indicating that phosphorylation of Pah1p controls PA production. Opi1p is a transcriptional repressor of phospholipid biosynthetic genes, responding to PA levels. Genetic analysis suggests that Pah1p regulates transcription of these genes through both Opi1p-dependent and -independent mechanisms. We also provide evidence that derepression of phospholipid biosynthetic genes is not sufficient to induce the nuclear membrane expansion shown in the pah1delta cells.
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http://dx.doi.org/10.1074/jbc.M606654200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769310PMC
November 2006

Affinity purification of Ypt6 effectors and identification of TMF/ARA160 as a Rab6 interactor.

Methods Enzymol 2005 ;403:599-607

Rab/Ypt GTPases are key regulators of intracellular traffic in eukaryotic cells. One important function of Rab/Ypts is the nucleotide-dependent recruitment of downstream effector molecules onto the membrane of organelles. In budding yeast Ypt6 is required for recycling of membrane proteins from endosomes back to the Golgi. A biochemical approach based on the affinity purification of Ypt6:GTP-interacting proteins from yeast cytosol led to the identification of two conserved Ypt6 effectors, the tetrameric VFT complex and Sgm1. The mammalian homolog of Sgm1, TMF/ARA160, contains a short conserved coiled-coil motif that is sufficient for the binding to the three mammalian orthologs of Ypt6, Rab6A, Rab6A', and Rab6B.
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http://dx.doi.org/10.1016/S0076-6879(05)03052-1DOI Listing
April 2006

The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth.

EMBO J 2005 Jun 5;24(11):1931-41. Epub 2005 May 5.

WellcomeTrust/Cancer Research UK Gurdon Institute, Cambridge, UK.

Remodelling of the nuclear membrane is essential for the dynamic changes of nuclear architecture at different stages of the cell cycle and during cell differentiation. The molecular mechanism underlying the regulation of nuclear membrane biogenesis is not known. Here we show that Smp2, the yeast homologue of mammalian lipin, is a key regulator of nuclear membrane growth during the cell cycle. Smp2 is phosphorylated by Cdc28/Cdk1 and dephosphorylated by a nuclear/endoplasmic reticulum (ER) membrane-localized CPD phosphatase complex consisting of Nem1 and Spo7. Loss of either SMP2 or its dephosphorylated form causes transcriptional upregulation of key enzymes involved in lipid biosynthesis concurrent with a massive expansion of the nucleus. Conversely, constitutive dephosphorylation of Smp2 inhibits cell division. We show that Smp2 associates with the promoters of phospholipid biosynthetic enzymes in a Nem1-Spo7-dependent manner. Our data suggest that Smp2 is a critical factor in coordinating phospholipid biosynthesis at the nuclear/ER membrane with nuclear growth during the cell cycle.
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http://dx.doi.org/10.1038/sj.emboj.7600672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142606PMC
June 2005