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Mol Cell Biol. Dec 1996; 16(12): 7161–7172.
PMCID: PMC231720

A yeast acetyl coenzyme A carboxylase mutant links very-long-chain fatty acid synthesis to the structure and function of the nuclear membrane-pore complex.

Abstract

The conditional mRNA transport mutant of Saccharomyces cerevisiae, acc1-7-1 (mtr7-1), displays a unique alteration of the nuclear envelope. Unlike nucleoporin mutants and other RNA transport mutants, the intermembrane space expands, protuberances extend from the inner membrane into the intermembrane space, and vesicles accumulate in the intermembrane space. MTR7 is the same gene as ACC1, encoding acetyl coenzyme A (CoA) carboxylase (Acc1p), the rate-limiting enzyme of de novo fatty acid synthesis. Genetic and biochemical analyses of fatty acid synthesis mutants and acc1-7-1 indicate that the continued synthesis of malonyl-CoA, the enzymatic product of acetyl-CoA carboxylase, is required for an essential pathway which is independent from de novo synthesis of fatty acids. We provide evidence that synthesis of very-long-chain fatty acids (C26 atoms) is inhibited in acc1-7-1, suggesting that very-long-chain fatty acid synthesis is required to maintain a functional nuclear envelope.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957–3961. [PMC free article] [PubMed]
  • Al-Feel W, Chirala SS, Wakil SJ. Cloning of the yeast FAS3 gene and primary structure of yeast acetyl-CoA carboxylase. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4534–4538. [PMC free article] [PubMed]
  • Allan D, Raval PJ. A sphingomyelinase-resistant pool of sphingomyelin in the nuclear membrane of hen erythrocytes. Biochim Biophys Acta. 1987 Mar 12;897(3):355–363. [PubMed]
  • Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. [PubMed]
  • Aris JP, Blobel G. Identification and characterization of a yeast nucleolar protein that is similar to a rat liver nucleolar protein. J Cell Biol. 1988 Jul;107(1):17–31. [PMC free article] [PubMed]
  • Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD, et al. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):80–84. [PMC free article] [PubMed]
  • Bishop WR, Bell RM. Assembly of phospholipids into cellular membranes: biosynthesis, transmembrane movement and intracellular translocation. Annu Rev Cell Biol. 1988;4:579–610. [PubMed]
  • Bloom M, Evans E, Mouritsen OG. Physical properties of the fluid lipid-bilayer component of cell membranes: a perspective. Q Rev Biophys. 1991 Aug;24(3):293–397. [PubMed]
  • Bogerd AM, Hoffman JA, Amberg DC, Fink GR, Davis LI. nup1 mutants exhibit pleiotropic defects in nuclear pore complex function. J Cell Biol. 1994 Oct;127(2):319–332. [PMC free article] [PubMed]
  • Bonneaud N, Ozier-Kalogeropoulos O, Li GY, Labouesse M, Minvielle-Sebastia L, Lacroute F. A family of low and high copy replicative, integrative and single-stranded S. cerevisiae/E. coli shuttle vectors. Yeast. 1991 Aug-Sep;7(6):609–615. [PubMed]
  • Brown MS, Faust JR, Goldstein JL, Kaneko I, Endo A. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J Biol Chem. 1978 Feb 25;253(4):1121–1128. [PubMed]
  • Cane DE. Polyketide biosynthesis: molecular recognition or genetic programming? Science. 1994 Jan 21;263(5145):338–340. [PubMed]
  • Carlson M, Botstein D. Two differentially regulated mRNAs with different 5' ends encode secreted with intracellular forms of yeast invertase. Cell. 1982 Jan;28(1):145–154. [PubMed]
  • Chirala SS, Zhong Q, Huang W, al-Feel W. Analysis of FAS3/ACC regulatory region of Saccharomyces cerevisiae: identification of a functional UASINO and sequences responsible for fatty acid mediated repression. Nucleic Acids Res. 1994 Feb 11;22(3):412–418. [PMC free article] [PubMed]
  • Cinti DL, Cook L, Nagi MN, Suneja SK. The fatty acid chain elongation system of mammalian endoplasmic reticulum. Prog Lipid Res. 1992;31(1):1–51. [PubMed]
  • Conzelmann A, Puoti A, Lester RL, Desponds C. Two different types of lipid moieties are present in glycophosphoinositol-anchored membrane proteins of Saccharomyces cerevisiae. EMBO J. 1992 Feb;11(2):457–466. [PMC free article] [PubMed]
  • Dekker CJ, Geurts van Kessel WS, Klomp JP, Pieters J, De Kruijff B. Synthesis and polymorphic phase behaviour of polyunsaturated phosphatidylcholines and phosphatidylethanolamines. Chem Phys Lipids. 1983 Jul;33(1):93–106. [PubMed]
  • Dietlein G, Schweizer E. Control of fatty-acid synthetase biosynthesis in Saccharomyces cerevisiae. Eur J Biochem. 1975 Oct 1;58(1):177–184. [PubMed]
  • Dingwall C, Laskey R. The nuclear membrane. Science. 1992 Nov 6;258(5084):942–947. [PubMed]
  • Doye V, Wepf R, Hurt EC. A novel nuclear pore protein Nup133p with distinct roles in poly(A)+ RNA transport and nuclear pore distribution. EMBO J. 1994 Dec 15;13(24):6062–6075. [PMC free article] [PubMed]
  • Evan GI, Lewis GK, Ramsay G, Bishop JM. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. [PMC free article] [PubMed]
  • Fulco AJ. Chain elongation, 20hydroxylation, and decarboxylation of long chain fatty acids by yeast. J Biol Chem. 1967 Aug 25;242(16):3608–3613. [PubMed]
  • Gorsch LC, Dockendorff TC, Cole CN. A conditional allele of the novel repeat-containing yeast nucleoporin RAT7/NUP159 causes both rapid cessation of mRNA export and reversible clustering of nuclear pore complexes. J Cell Biol. 1995 May;129(4):939–955. [PMC free article] [PubMed]
  • Greber UF, Gerace L. Nuclear protein import is inhibited by an antibody to a lumenal epitope of a nuclear pore complex glycoprotein. J Cell Biol. 1992 Jan;116(1):15–30. [PMC free article] [PubMed]
  • Guerra CE, Klein HL. Mapping of the ACC1/FAS3 gene to the right arm of chromosome XIV of Saccharomyces cerevisiae. Yeast. 1995 Jun 15;11(7):697–700. [PubMed]
  • Hampton RY, Rine J. Regulated degradation of HMG-CoA reductase, an integral membrane protein of the endoplasmic reticulum, in yeast. J Cell Biol. 1994 Apr;125(2):299–312. [PMC free article] [PubMed]
  • Hardie DG. Regulation of fatty acid synthesis via phosphorylation of acetyl-CoA carboxylase. Prog Lipid Res. 1989;28(2):117–146. [PubMed]
  • Hasslacher M, Ivessa AS, Paltauf F, Kohlwein SD. Acetyl-CoA carboxylase from yeast is an essential enzyme and is regulated by factors that control phospholipid metabolism. J Biol Chem. 1993 May 25;268(15):10946–10952. [PubMed]
  • Hechtberger P, Daum G. Intracellular transport of inositol-containing sphingolipids in the yeast, Saccharomyces cerevisiae. FEBS Lett. 1995 Jun 26;367(2):201–204. [PubMed]
  • Higgins MJ, Kekwick RG. An investigation into the role of malonyl-coenzyme A in isoprenoid biosynthesis. Biochem J. 1973 May;134(1):295–310. [PMC free article] [PubMed]
  • Hopwood DA, Sherman DH. Molecular genetics of polyketides and its comparison to fatty acid biosynthesis. Annu Rev Genet. 1990;24:37–66. [PubMed]
  • Hori T, Nakamura N, Okuyama H. Possible involvement of acetyl coenzyme A carboxylase as well as fatty acid synthetase in the temperature-controlled synthesis of fatty acids in Saccharomyces cerevisiae. J Biochem. 1987 Apr;101(4):949–956. [PubMed]
  • Hui SW, Mason JT, Huang C. Acyl chain interdigitation in saturated mixed-chain phosphatidylcholine bilayer dispersions. Biochemistry. 1984 Nov 6;23(23):5570–5577. [PubMed]
  • Israelachvili JN, Marcelja S, Horn RG. Physical principles of membrane organization. Q Rev Biophys. 1980 May;13(2):121–200. [PubMed]
  • Ito H, Fukuda Y, Murata K, Kimura A. Transformation of intact yeast cells treated with alkali cations. J Bacteriol. 1983 Jan;153(1):163–168. [PMC free article] [PubMed]
  • Jandrositz A, Turnowsky F, Högenauer G. The gene encoding squalene epoxidase from Saccharomyces cerevisiae: cloning and characterization. Gene. 1991 Oct 30;107(1):155–160. [PubMed]
  • Johnson DR, Knoll LJ, Levin DE, Gordon JI. Saccharomyces cerevisiae contains four fatty acid activation (FAA) genes: an assessment of their role in regulating protein N-myristoylation and cellular lipid metabolism. J Cell Biol. 1994 Nov;127(3):751–762. [PMC free article] [PubMed]
  • Kadowaki T, Chen S, Hitomi M, Jacobs E, Kumagai C, Liang S, Schneiter R, Singleton D, Wisniewska J, Tartakoff AM. Isolation and characterization of Saccharomyces cerevisiae mRNA transport-defective (mtr) mutants. J Cell Biol. 1994 Aug;126(3):649–659. [PMC free article] [PubMed]
  • Kadowaki T, Zhao Y, Tartakoff AM. A conditional yeast mutant deficient in mRNA transport from nucleus to cytoplasm. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2312–2316. [PMC free article] [PubMed]
  • Kohlwein SD, Paltauf F. Uptake of fatty acids by the yeasts, Saccharomyces uvarum and Saccharomycopsis lipolytica. Biochim Biophys Acta. 1984 Mar 7;792(3):310–317. [PubMed]
  • Köttig H, Rottner G, Beck KF, Schweizer M, Schweizer E. The pentafunctional FAS1 genes of Saccharomyces cerevisiae and Yarrowia lipolytica are co-linear and considerably longer than previously estimated. Mol Gen Genet. 1991 Apr;226(1-2):310–314. [PubMed]
  • Kranz JE, Holm C. Cloning by function: an alternative approach for identifying yeast homologs of genes from other organisms. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6629–6633. [PMC free article] [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Lester RL, Dickson RC. Sphingolipids with inositolphosphate-containing head groups. Adv Lipid Res. 1993;26:253–274. [PubMed]
  • Lester RL, Wells GB, Oxford G, Dickson RC. Mutant strains of Saccharomyces cerevisiae lacking sphingolipids synthesize novel inositol glycerophospholipids that mimic sphingolipid structures. J Biol Chem. 1993 Jan 15;268(2):845–856. [PubMed]
  • Li O, Heath CV, Amberg DC, Dockendorff TC, Copeland CS, Snyder M, Cole CN. Mutation or deletion of the Saccharomyces cerevisiae RAT3/NUP133 gene causes temperature-dependent nuclear accumulation of poly(A)+ RNA and constitutive clustering of nuclear pore complexes. Mol Biol Cell. 1995 Apr;6(4):401–417. [PMC free article] [PubMed]
  • Lohner K. Effects of small organic molecules on phospholipid phase transitions. Chem Phys Lipids. 1991 Mar;57(2-3):341–362. [PubMed]
  • Mackall JC, Lane MD, Leonard KR, Pendergast M, Kleinschmidt AK. Subunit size and paracrystal structure of avian liver acetyl-CoA carboxylase. J Mol Biol. 1978 Aug 25;123(4):595–606. [PubMed]
  • Mirzayan C, Copeland CS, Snyder M. The NUF1 gene encodes an essential coiled-coil related protein that is a potential component of the yeast nucleoskeleton. J Cell Biol. 1992 Mar;116(6):1319–1332. [PMC free article] [PubMed]
  • Mishina M, Roggenkamp R, Schweizer E. Yeast mutants defective in acetyl-coenzyme A carboxylase and biotin: apocarboxylase ligase. Eur J Biochem. 1980 Oct;111(1):79–87. [PubMed]
  • Mohamed AH, Chirala SS, Mody NH, Huang WY, Wakil SJ. Primary structure of the multifunctional alpha subunit protein of yeast fatty acid synthase derived from FAS2 gene sequence. J Biol Chem. 1988 Sep 5;263(25):12315–12325. [PubMed]
  • Mouritsen OG, Bloom M. Mattress model of lipid-protein interactions in membranes. Biophys J. 1984 Aug;46(2):141–153. [PMC free article] [PubMed]
  • Mutvei A, Dihlmann S, Herth W, Hurt EC. NSP1 depletion in yeast affects nuclear pore formation and nuclear accumulation. Eur J Cell Biol. 1992 Dec;59(2):280–295. [PubMed]
  • Nurminen T, Suomalainen H. Occurrence of long-chain fatty acids and glycolipids in the cell envelope fractions of baker's yeast. Biochem J. 1971 Dec;125(4):963–969. [PMC free article] [PubMed]
  • Omura S. Cerulenin. Methods Enzymol. 1981;72:520–532. [PubMed]
  • Pagano RE. Lipid traffic in eukaryotic cells: mechanisms for intracellular transport and organelle-specific enrichment of lipids. Curr Opin Cell Biol. 1990 Aug;2(4):652–663. [PubMed]
  • Patton JL, Lester RL. The phosphoinositol sphingolipids of Saccharomyces cerevisiae are highly localized in the plasma membrane. J Bacteriol. 1991 May;173(10):3101–3108. [PMC free article] [PubMed]
  • Pearson WR, Lipman DJ. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. [PMC free article] [PubMed]
  • Pinto WJ, Srinivasan B, Shepherd S, Schmidt A, Dickson RC, Lester RL. Sphingolipid long-chain-base auxotrophs of Saccharomyces cerevisiae: genetics, physiology, and a method for their selection. J Bacteriol. 1992 Apr;174(8):2565–2574. [PMC free article] [PubMed]
  • Riles L, Dutchik JE, Baktha A, McCauley BK, Thayer EC, Leckie MP, Braden VV, Depke JE, Olson MV. Physical maps of the six smallest chromosomes of Saccharomyces cerevisiae at a resolution of 2.6 kilobase pairs. Genetics. 1993 May;134(1):81–150. [PMC free article] [PubMed]
  • Roggenkamp R, Numa S, Schweizer E. Fatty acid-requiring mutant of Saccharomyces cerevisiae defective in acetyl-CoA carboxylase. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1814–1817. [PMC free article] [PubMed]
  • Rothstein R. Targeting, disruption, replacement, and allele rescue: integrative DNA transformation in yeast. Methods Enzymol. 1991;194:281–301. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Schneider P, Ferguson MA, McConville MJ, Mehlert A, Homans SW, Bordier C. Structure of the glycosyl-phosphatidylinositol membrane anchor of the Leishmania major promastigote surface protease. J Biol Chem. 1990 Oct 5;265(28):16955–16964. [PubMed]
  • Schweizer E, Bolling H. A Saccharomyces cerevisiae mutant defective in saturated fatty acid biosynthesis. Proc Natl Acad Sci U S A. 1970 Oct;67(2):660–666. [PMC free article] [PubMed]
  • Schweizer E, Kniep B, Castorph H, Holzner U. Pantetheine-free mutants of the yeast fatty-acid-synthetase complex. Eur J Biochem. 1973 Nov 15;39(2):353–362. [PubMed]
  • Severs NJ, Jordan EG, Williamson DH. Nuclear pore absence from areas of close association between nucleus and vacuole in synchronous yeast cultures. J Ultrastruct Res. 1976 Mar;54(3):374–387. [PubMed]
  • Shen B, Hutchinson CR. Enzymatic synthesis of a bacterial polyketide from acetyl and malonyl coenzyme A. Science. 1993 Dec 3;262(5139):1535–1540. [PubMed]
  • Sikorski RS, Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. [PMC free article] [PubMed]
  • Silver PA, Chiang A, Sadler I. Mutations that alter both localization and production of a yeast nuclear protein. Genes Dev. 1988 Jun;2(6):707–717. [PubMed]
  • Stadler J, Keenan TW, Bauer G, Gerisch G. The contact site A glycoprotein of Dictyostelium discoideum carries a phospholipid anchor of a novel type. EMBO J. 1989 Feb;8(2):371–377. [PMC free article] [PubMed]
  • Stewart LC, Yaffe MP. A role for unsaturated fatty acids in mitochondrial movement and inheritance. J Cell Biol. 1991 Dec;115(5):1249–1257. [PMC free article] [PubMed]
  • Sumper M, Oesterhelt D, Riepertinger C, Lynen F. Die Synthese verschiedener Carbonsäuren durch den Multienzymkomplex der Fettsäuresynthese aus Hefe und die Erklärung ihrer Bildung. Eur J Biochem. 1969 Sep;10(2):377–387. [PubMed]
  • Toh H, Kondo H, Tanabe T. Molecular evolution of biotin-dependent carboxylases. Eur J Biochem. 1993 Aug 1;215(3):687–696. [PubMed]
  • Wagner S, Paltauf F. Generation of glycerophospholipid molecular species in the yeast Saccharomyces cerevisiae. Fatty acid pattern of phospholipid classes and selective acyl turnover at sn-1 and sn-2 positions. Yeast. 1994 Nov;10(11):1429–1437. [PubMed]
  • Wells GB, Lester RL. The isolation and characterization of a mutant strain of Saccharomyces cerevisiae that requires a long chain base for growth and for synthesis of phosphosphingolipids. J Biol Chem. 1983 Sep 10;258(17):10200–10203. [PubMed]
  • Wente SR, Blobel G. A temperature-sensitive NUP116 null mutant forms a nuclear envelope seal over the yeast nuclear pore complex thereby blocking nucleocytoplasmic traffic. J Cell Biol. 1993 Oct;123(2):275–284. [PMC free article] [PubMed]
  • Wente SR, Blobel G. NUP145 encodes a novel yeast glycine-leucine-phenylalanine-glycine (GLFG) nucleoporin required for nuclear envelope structure. J Cell Biol. 1994 Jun;125(5):955–969. [PMC free article] [PubMed]
  • Wente SR, Rout MP, Blobel G. A new family of yeast nuclear pore complex proteins. J Cell Biol. 1992 Nov;119(4):705–723. [PMC free article] [PubMed]
  • Willison JH, Johnston GC. Altered nuclear pore diameters in G1-arrested cells of the yeast Saccharomyces cerevisiae. J Bacteriol. 1978 Oct;136(1):318–323. [PMC free article] [PubMed]
  • Witters LA, Watts TD. Yeast acetyl-CoA carboxylase: in vitro phosphorylation by mammalian and yeast protein kinases. Biochem Biophys Res Commun. 1990 Jun 15;169(2):369–376. [PubMed]
  • Wozniak RW, Blobel G, Rout MP. POM152 is an integral protein of the pore membrane domain of the yeast nuclear envelope. J Cell Biol. 1994 Apr;125(1):31–42. [PMC free article] [PubMed]
  • Yaffe MP, Schatz G. Two nuclear mutations that block mitochondrial protein import in yeast. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4819–4823. [PMC free article] [PubMed]

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