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PubMed1978

Effect of thyroid phospholipids on the interaction of thyrotropin with thyroid membranes.

Various lipids extracted from bovine thyroid glands were tested for their ability to affect the binding of 125I-labeled thyrotropin to bovine thyroid membranes. The most potent inhibitors were the acidic phospholipids in the order cardiolipin greater than phosphatidylglycerol greater than phosphatidylinositol greater than phosphatidylserine. Other phospholipids, neutral lipids, and neutral glycolipids were ineffective. As reported previously [mullin, B. R., Pacuszka, T., Lee, G., Kohn, L. D., Brady, R. O. & Fishman, P. H. (1978) Science 199, 77--79], thyroid gangliosides also inhibited thyrotropin binding but not as effectively as phospholipids. In addition, the mode of action of these two classes of acidic lipids was different. When thyroid membranes were preincubated with the phospholipids and then separated by centrifugation, their ability to bind thyrotropin was still diminished. In contrast, gangliosides appear to interact with the hormone and not with the membranes. The effect of phospholipids on thyroid membranes was further examined by incubating the membranes with phospholipase A. The treated membranes now bound more labeled hormone. These results suggest that certain acidic phospholipids, which are present in only small amounts in thyroid membranes, influence the state of the thyrotropin receptor and its ability to bind thyrotropin.

Animals↗
PubMed1979

Chemoattractants stimulate degradation of methylated phospholipids and release of arachidonic acid in rabbit leukocytes.

When rabbit peritoneal leukocytes were treated with chemoattractants such as fMet-Leu-Phe, an apparent decrease of [3H]methyl incorporation into the lipid fraction from L-[methyl-3H]methionine was observed. This decrease was a result of increased degradation of methylated phospholipids, not of decreased synthesis. Chemotactic peptides did not affect the metabolism of the phospholipids in which [methyl-14C]choline was incorporated. The disappearance of the [3H]methyl group was associated with the release of [1-14C]arachidonic acid from phospholipids prelabeled with these compounds. These findings suggested the activation by chemoattractants of phospholipase A2, an enzyme that removes an unsaturated fatty acid from phospholipids. The order of potency of chemoattractants for the stimulated degradation of phospholipids was in good agreement with that for chemotaxis. Mepacrine (quinacrine) and hydrocortisone inhibited and a phorbol ester enhanced both chemotaxis and phospholipase A2 activity. These results, taken together, suggest close association of the metabolism of methylated phospholipids with chemotaxis in rabbit peritoneal leukocytes.

Animals↗
PubMed1980

Phospholipids as the molecular instruments of ion and solute transport in biological membranes.

Partition studies have established that phospholipids generally have the capabilities to mediate the transmembrane transport of the full range of ions and solutes that physiologically cross biological membranes. The list of transportable species includes cations, anions, amino acids, citric acid cycle intermediates, nucleotides, and sugars. Phospholipid-mediated transport can be readily modulated by altering the phospholipid mixture or by addition of detergents, nucleotides, divalent metals, proteins, peptides, or ring compounds. Containment of phospholipid within channels in protein appears to be the precondition for the formation of the micellar structure requisite for solute transport. Phospholipid-mediated transport is postulated to be a central feature of energy coupling, membrane-spanning systems, and membrane-bound, phospholipid-requiring enzymes.

Biological Transport↗
PubMed1982

Corticotropin-releasing factor stimulates phospholipid methylation and corticotropin secretion in mouse pituitary tumor cells.

The 41-residue synthetic ovine corticotropin-releasing factor (CRF; corticoliberin) has been shown to stimulate release of corticotropin (adrenocorticotropic hormone; ACTH) and beta-endorphin from AtT-20/D16-16 mouse pituitary tumor cells. Phospholipid methylation of phosphatidylethanolamine to phosphatidylcholine with S-adenosylmethionine as methyl donor has been suggested as a possible membrane transduction mechanism for some receptor-induced events. CRF increased phospholipid methylation in pituitary tumor cells at concentrations that also stimulated immunoreactive ACTH secretion, and both processes increased linearly and in parallel with time. The methionine sulfoxide derivative of CRF was less potent than CRF was in stimulating both phospholipid methylation and hormone secretion, and the COOH-terminal free acid analogue of CRF had no effect on either process. CRF-induced increases in phospholipid methylation and ACTH secretion were reduced when cells were treated with the phospholipid methyltransferase inhibitors 3-deazaadenosine and L-homocysteine thiolactone. These CRF-stimulated effects were also blocked by the glucocorticoid dexamethasone. It is suggested that phospholipid methylation may be a CRF receptor-mediated event associated with ACTH release in pituitary tumor cells.

Adrenocorticotropic Hormone↗
PubMed1983

Activation of the heme-stabilized translational inhibitor of reticulocyte lysates by calcium ions and phospholipid.

Hemin-supplemented reticulocyte lysates can be activated for translational inhibition by addition of Ca2+ or phospholipid. The fact that this inhibition is prevented or decreased in both cases either by the Ca2+ chelator EGTA or by polymyxin B, an inhibitor of the recently described Ca2+- and phospholipid-dependent protein kinases, suggests the involvement of both Ca2+ and phospholipid in this activation. The inhibition by Ca2+ or phospholipid is accompanied by phosphorylation of the 38-kilodalton subunit of the eukaryotic initiation factor 2 (eIF-2) and the 90-kilodalton band of the heme-controlled translational inhibitor (HCI) and can be reversed by high concentrations of eIF-2 or GTP. When incubation is conducted at 30 degrees C, the inhibition produced by Ca2+ is not reversed by EGTA after 15 min. However, at 20 degrees C, Ca2+ inhibition can be fully reversed as late as 90 min from the start of incubation and phosphorylation of the eIF-2 alpha-subunit is correspondingly decreased. These results are consistent with the idea that, like heme deprivation, the activation by Ca2+ and phospholipid promotes the first step of the reaction pro-inhibitor in equilibrium reversible inhibitor leads to irreversible inhibitor and suggest that, in the presence of hemin albeit by a different mechanism, this activation affects the same inhibitor that is activated in the absence of heme--namely, HCI. Whether this activation is direct or indirect--e.g., via a separate Ca2+- and phospholipid-dependent protein kinase--remains to be determined.

Animals↗
PubMed1983

Coordinate regulation of unsaturated phospholipid, RNA, and protein synthesis in Mycoplasma capricolum by cholesterol.

The effect of cholesterol, epicoprostanol, and phosphatidylcholine on phospholipid, RNA, and protein synthesis was investigated in the sterol auxotroph Mycoplasma capricolum. Cells growing poorly on lanosterol were stimulated to grow more rapidly by supplementing the medium with either 2 micrograms of cholesterol or 2.2 micrograms of egg phosphatidylcholine per ml. In such cells cholesterol caused a sequential stimulation of phospholipid, RNA, and protein synthesis. Enhanced oleate incorporation into phospholipid occurred early; the rates of RNA and protein synthesis increased later. In cells supplemented with phosphatidylcholine only RNA and protein syntheses were enhanced. The addition of 2 micrograms of epicoprostanol per ml to cells growing on lanosterol promptly inhibited the rate of unsaturated phospholipid synthesis and subsequently the rate of growth. Inhibition of both processes was relieved by supplying 2 micrograms of cholesterol or 2.2 micrograms of phosphatidylcholine per ml along with the inhibitory sterol. The results suggest that cholesterol in small amounts exerts a positive regulatory effect and epicoprostanol exerts a negative one on unsaturated phospholipid synthesis and, in turn, that RNA and protein synthesis are coordinately controlled with phospholipid synthesis. The previously reported phenomenon of sterol synergism and the postulated novel role of sterols in membranes.

Bacterial Proteins↗
PubMed1989

Phospholipids containing polyunsaturated fatty acyl groups are mitogenic for normal mouse mammary epithelial cells in serum-free primary cell culture.

Epithelial cells obtained by collagenase digestion of mammary glands from virgin BALB/c mice were cultured in collagen gels in serum-free basal medium containing insulin (10 micrograms/ml), to which lipids or growth factors were added. Synthetic phospholipids were added as liposomes. Dilinoleoyl phosphatidic acid or phosphatidylserine or epidermal growth factor stimulated multifold growth. The optimum mitogenic effect of the phospholipids was dependent upon the presence of a polyunsaturated fatty acid esterified to the sn-2 position of the glycerol moiety. Dilinoleoyl phosphatidylcholine also stimulated growth but was generally less stimulatory than phosphatidylserine or phosphatidic acid, and phosphatidylethanolamine did not stimulate growth. Studies using phospholipids radiolabeled in either the sn-2 fatty acyl group or the glycerol backbone showed that the relative effect of phospholipids on growth did not correlate directly with the extent of their incorporation into cellular lipid, indicating that phospholipid turnover was the more important determinant for mitogenesis. Analysis of phosphatidic acid-stimulated growth suggested that both cAMP-dependent and cAMP-independent pathways were involved. Thus, mitogenic phospholipids stimulate proliferation by activating (directly or indirectly) multiple growth-regulatory pathways in mammary epithelial cells.

1-Methyl-3-isobutylxanthine↗
PubMed1995

The beta-adrenergic receptor kinase (GRK2) is regulated by phospholipids.

The beta-adrenergic receptor kinase (beta ARK) is a member of growing family of G protein coupled receptor kinases (GRKs). beta ARK and other members of the GRK family play a role in the mechanism of agonist-specific desensitization by virtue of their ability to phosphorylate G protein-coupled receptors in an agonist-dependent manner. beta ARK activation is known to occur following the interaction of the kinase with the agonist-occupied form of the receptor substrate and heterotrimeric G protein beta gamma subunits. Recently, lipid regulation of GRK2, GRK3, and GRK5 have also been described. Using a mixed micelle assay, GRK2 (beta ARK1) was found to require phospholipid in order to phosphorylate the beta 2-adrenergic receptor. As determined with a nonreceptor peptide substrate of beta ARK, catalytic activity of the kinase increased in the presence of phospholipid without a change in the Km for the peptide. Data obtained with the heterobifunctional cross-linking agent N-3-[125I]iodo-4-azidophenylpropionamido-S-(2-thiopyridyl)-c ysteine ([125I]ACTP) suggests that the activation by phospholipid was associated with a conformational change in the kinase. [125I]ACTP incorporation increased 2-fold in the presence of crude phosphatidylcholine, and this increase in [125I]ACTP labeling is completely blocked by the addition of MgATP. Furthermore, proteolytic mapping was consistent with the modification of a distinct site when GRK2 was labeled in the presence of phospholipid. While an acidic phospholipid specificity was demonstrated using the mixed micelle phosphorylation assay, a notable exception was observed with PIP2. In the presence of PIP2, kinase activity as well as [125I]ACTP labeling was inhibited. These data demonstrate the direct regulation of GRK2 activity by phospholipids and supports the hypothesis that this effect is the result of a conformational change within the kinase.

Amino Acid Sequence↗
PubMed1996

Acylation of pulmonary surfactant protein-C is required for its optimal surface active interactions with phospholipids.

This study investigates the importance of thioester-linked acyl groups in lung surfactant protein C (SP-C) in facilitating interactions with phospholipids that yield functionally important surface active behaviors. Native SP-C, palmitoylated at cysteine residues at positions 5 and 6, was isolated from bovine lung surfactant by liquid chromatography. Deacylated SP-C (dSP-C), unchanged in composition and sequence from SP-C but having a decreased alpha-helical content in films with dipalmitoyl phosphatidylcholine (DPPC) of 52 versus 70%, was obtained by treatment with 0.1 M sodium carbonate buffer at pH 10. Surface activity was studied for SP-C and dSP-C combined with column-purified phospholipids (PPL) from calf lung surfactant or with synthetic phospholipids (DPPC or a synthetic phospholipid mixture (SPL) containing 50:35:15, DPPC:egg phosphatidylcholine:egg phosphatidylglycerol). Interfacial measurements included surface pressure time adsorption isotherms for dispersed surfactants with diffusion minimized, dynamic surface pressure area isotherms and respreading for films in the Wilhelmy balance, and overall surface tension lowering at physiologic cycling rate in oscillating bubble experiments. Dispersions of PPL:SP-C and SPL:SP-C rapidly adsorbed to high equilibrium surface pressures of 47-48 mN/m, significantly better than corresponding dispersions containing dSP-C. The adsorption of PPL:dSP-C was essentially unchanged from that of PPL alone, and the adsorption of SPL:dSP-C was improved only slightly over SPL alone. In Wilhelmy balance studies, dynamic respreading was significantly improved over phospholipids alone in films of SP-C plus PPL, SPL, or DPPC. Respreading was improved less markedly by dSP-C in corresponding films with SPL or DPPC and not at all in films with PPL. Maximum surface pressures were also higher in cycled films of SP-C versus dSP-C combined with PPL or SPL. In bubble experiments (37 degrees C, 20 cycles/min), dispersions of PPL:SP-C and SPL:SP-C reached low minimum surface tensions of <1 and 5 mN/m, respectively, whereas PPL:dSP-C and SPL:dSP-C only reached minima of approximately 20 mN/m as did PPL and SPL alone. Acylation in SP-C is crucial for its interactions with phospholipids over the full spectrum of adsorption and dynamic surface behaviors important for lung surfactant.

Acylation↗
PubMed1997

Role of protein-phospholipid interactions in the activation of ARF1 by the guanine nucleotide exchange factor Arno.

Arno is a 47-kDa human protein recently identified as a guanine nucleotide exchange factor for ADP ribosylation factor 1 (ARF1) with a central Sec7 domain responsible for the exchange activity and a carboxyl-terminal pleckstrin homology (PH) domain (Chardin, P., Paris, S., Antonny, B., Robineau, S., Béraud-Dufour, S., Jackson, C. L., and Chabre, M. (1996) Nature 384, 481-484). Binding of the PH domain to phosphatidylinositol 4,5-bisphosphate (PIP2) greatly enhances Arno-mediated activation of myristoylated ARF1. We show here that in the absence of phospholipids, Arno promotes nucleotide exchange on [Delta17]ARF1, a soluble mutant of ARF1 lacking the first 17 amino acids. This reaction is unaffected by PIP2, which suggests that the PIP2-PH domain interaction does not directly regulate the catalytic activity of Arno but rather serves to recruit Arno to membranes. Arno catalyzes the release of GDP more efficiently than that of GTP from [Delta17]ARF1, and a stable complex between Arno Sec7 domain and nucleotide-free [Delta17]ARF1 can be isolated. In contrast to [Delta17]ARF1, full-length unmyristoylated ARF1 is not readily activated by Arno in solution. Its activation requires the presence of phospholipids and a reduction of ionic strength and Mg2+ concentration. PIP2 is strongly stimulatory, indicating that binding of Arno to phospholipids is involved, but in addition, electrostatic interactions between phospholipids and the amino-terminal portion of unmyristoylated ARF1GDP seem to be important. We conclude that efficient activation of full-length ARF1 by Arno requires a membrane surface and two distinct protein-phospholipid interactions: one between the PH domain of Arno and PIP2, and the other between amino-terminal cationic residues of ARF1 and anionic phospholipids. The latter interaction is normally induced by insertion of the amino-terminal myristate into the bilayer but can also be artificially facilitated by decreasing Mg2+ and salt concentrations.

ADP-Ribosylation Factor 1↗
PubMed1997

Anionic phospholipids activate ATP-sensitive potassium channels.

The ATP-sensitive potassium channel (KATP) controls insulin release in pancreatic beta-cells and also modulates important functions in other cell types. In this study we report that anionic phospholipids activated KATP in pancreatic beta-cells, cardiac myocytes, skeletal muscle cells, and a cloned KATP composed of two subunits (SUR/Kir6. 2) stably expressed in a mammalian cell line. The effectiveness was proportional to the number of negative charges on the head group of the anionic phospholipid. Screening negative charges with polyvalent cations antagonized the effect. Enzymatic treatment with phospholipases that reduced charge on the lipids also reduced or eliminated the effect. These results suggest that intact phospholipids with negative charges are the critical requirement for activation of KATP, in distinction from the usual cell signaling pathway through phospholipids that requires cleavage. Mutations of two positively charged amino acid residues at the C terminus of Kir6. 2 accelerated loss of channel activity and reduced the activating effects of phospholipids, suggesting involvement of this region in the activation. Metabolism of anionic phospholipids in plasmalemmal membrane may be a novel and general mechanism for regulation of KATP and perhaps other ion channels in the family of inward rectifiers.

ATP-Binding Cassette Transporters↗
PubMed1998

Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors.

We recently reported that the rate of efflux of cholesterol from cells to high density lipoprotein (HDL) was related to the expression level of scavenger receptor class B type I (SR-BI). Moreover, the expression of this receptor in atheromatous arteries raises the possibility that SR-BI mediates cholesterol efflux in the arterial wall (Ji, Y., Jian, B., Wang, N., Sun, Y., de la Llera Moya, M., Phillips, M. C., Rothblat, G. H., Swaney, J. B., and Tall, A. R. (1997) J. Biol. Chem. 272, 20982-20985). In this paper we describe studies that suggest that the presence of phospholipid on acceptor particles plays an important role in modulating interaction with the SR-BI. Specifically, enrichment of serum with phospholipid resulted in marked stimulation of cholesterol efflux from cells that had higher levels of SR-BI expression, like Fu5AH or Y1-BS1 cells, and little or no stimulation in cells with low SR-BI levels, such as Y-1 cells. Stimulation of efflux by phospholipid enrichment was also a function of SR-BI levels in Chinese hamster ovary cells transfected with the SR-BI gene. Efflux to protein-free vesicles prepared with 1-palmitoyl-2-oleoylphosphatidyl-choline also correlated with SR-BI levels, suggesting that phospholipid, as well as protein, influences the interaction that results in cholesterol efflux. By contrast, cholesterol efflux from a non-cell donor showed no stimulation consequent to phospholipid enrichment of the serum acceptor. These results may help to explain observations in the literature that document an increased risk of atherosclerosis in patients with depressed levels of HDL phospholipid even in the face of normal HDL cholesterol levels.

Animals↗
PubMed1999

Mapping the phospholipid-binding surface and translocation determinants of the C2 domain from cytosolic phospholipase A2.

Cytosolic phospholipase A2 (cPLA2) plays a key role in the generation of arachidonic acid, a precursor of potent inflammatory mediators. Intact cPLA2 is known to translocate in a calcium-dependent manner from the cytosol to the nuclear envelope and endoplasmic reticulum. We show here that the C2 domain of cPLA2 alone is sufficient for this calcium-dependent translocation in living cells. We have identified sets of exposed hydrophobic residues in loops known as calcium-binding region (CBR) 1 and CBR3, which surround the C2 domain calcium-binding sites, whose mutation dramatically decreased phospholipid binding in vitro without significantly affecting calcium binding. Mutation of a residue that binds calcium ions (D43N) also eliminated phospholipid binding. The same mutations that prevent phospholipid binding of the isolated C2 domain in vitro abolished the calcium-dependent translocation of cPLA2 to internal membranes in vivo, suggesting that the membrane targeting is driven largely by direct interactions with the phospholipid bilayer. Using fluorescence quenching by spin-labeled phospholipids for a series of mutants containing a single tryptophan residue at various positions in the cPLA2 C2 domain, we show that two of the calcium-binding loops, CBR1 and CBR3, penetrate in a calcium-dependent manner into the hydrophobic core of the phospholipid bilayer, establishing an anchor for docking the domain onto the membrane.

Biological Transport↗
PubMed1999

Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid.

Lipid-free apolipoprotein (apo) A-I contributes to the reverse transport of cholesterol from the periphery to the liver by solubilizing plasma membrane phospholipid and cholesterol. The features of the apolipoprotein required for this process are not understood and are addressed in the current study. Membrane microsolubilization of human fibroblasts is not specific for apo A-I; unlipidated apos A-II, C, and E incubated with the fibroblast monolayers at a saturating concentration of 50 micrograms/ml are all able to release cholesterol and phospholipid similarly. To determine the properties of the apolipoprotein that drive the process, apo A-I peptides spanning the entire sequence of the protein were utilized; the peptides correspond to the 11- and 22-residue amphipathic alpha-helical segments, as well as adjacent combinations of the helices. Of the 20 helical peptides examined, only peptides representing the N-and C-terminal portions of the protein had the ability to solubilize phospholipid and cholesterol. Cholesterol efflux to the most effective peptides, 44-65 and 209-241, was approximately 50 and 70%, respectively, of that to intact apo A-I. Deletion mutants of apo E and apo A-I were constructed that have reduced lipid binding affinities as compared with the intact molecule. The proteins, apo A-I (Delta222-243), apo A-I (Delta190-243), apo E3 (Delta192-299) and apo E4 (Delta192-299) all exhibited a decreased ability to remove cellular cholesterol and phospholipid. These decreases correlated with the reduced ability of these proteins to penetrate into a phospholipid monomolecular film. Overall, the results indicate that insertion of amphipathic alpha-helices between the plasma membrane phospholipid molecules is a required step in the mechanism of apolipoprotein-mediated cellular lipid efflux. Therefore the lipid binding ability of the apolipoprotein is critical for efficient membrane microsolubilization.

Apolipoproteins↗
PubMed1999

Polyamine regulation of plasma membrane phospholipid flip-flop during apoptosis.

During apoptosis, phosphatidylserine (PS) is moved from the plasma membrane inner leaflet to the outer leaflet where it triggers recognition and phagocytosis of the apoptotic cell. Although the mechanisms of PS appearance during apoptosis are not well understood, it is thought that declining activity of the aminophospholipid translocase and calcium-mediated, nonspecific flip-flop of phospholipids play a role. As previous studies in the erythrocyte ghost have shown that polyamines can alter flip-flop of phospholipids, we asked whether alterations in cellular polyamines in intact cells undergoing apoptosis would affect PS appearance, either by altering aminophospholipid translocase activity or phospholipid flip-flop. Cells of the human leukemic cell line, HL-60, were incubated with or without the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), and induced to undergo apoptosis by ultraviolet irradiation. Whereas DFMO treatment resulted in profound depletion of putrescine and spermidine (but not spermine), it had no effect on caspase activity, DNA fragmentation, or plasma membrane vesiculation, typical characteristics of apoptosis. Notably, DFMO treatment prior to ultraviolet irradiation did not alter the decline in PS inward movement by the aminophospholipid translocase as measured by the uptake of 6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminocaproyl] (NBD)-labeled PS detected in the flow cytometer. Conversely, the appearance of endogenous PS in the plasma membrane outer leaflet detected with fluorescein isothiocyanate-labeled annexin V and enhanced phospholipid flip-flop detected by the uptake of 1-palmitoyl-1-[6-[(7-nitro-2-1, 3-benzoxadiazol-4-yl)aminocaproyl]-sn-glycero-3-phosphocholine (NBD-PC) seen during apoptosis were significantly inhibited by prior DFMO treatment. Importantly, replenishment of spermidine, by treatment with exogenous putrescine to bypass the metabolic blockade by DFMO, restored both enhanced phospholipid flip-flop and appearance of PS during apoptosis. Such restoration was seen even in the presence of cycloheximide but was not seen when polyamines were added externally just prior to assay. Taken together, these data show that intracellular polyamines can modulate PS appearance resulting from nonspecific flip-flop of phospholipids across the plasma membrane during apoptosis.

Apoptosis↗
PubMed2002

Phospholipid-cytochrome c interaction: evidence for the extended lipid anchorage.

Binding of cytochrome c (cyt c) to fatty acids and acidic phospholipid membranes produces pronounced and essentially identical changes in the spectral properties of cyt c, revealing conformational changes in the protein. The exact mechanism of the interaction of fatty acids and acidic phospholipids with cyt c is unknown. Binding of cyt c to liposomes with high contents (mole fraction X > 0.7) of acidic phospholipids caused spectral changes identical to those due to binding of oleic acid. Fluorescence spectroscopy of a cyt c analog containing a Zn(2+) substituted heme moiety and brominated lipid derivatives (9,10)-dibromostearate and 1-palmitoyl-2-(9,10)-dibromo-sn-glycero-3-phospho-rac-glycerol demonstrated a direct contact between the fluorescent [Zn(2+)-heme] group and the brominated acyl chain. These data constitute direct evidence for interaction between an acyl chain of a membrane phospholipid and the inside of the protein containing the heme moiety and provide direct evidence for the so-called extended-lipid anchorage of cyt c to phospholipid membranes. In this mechanism, one of the phospholipid acyl chains protrudes out of the membrane and intercalates into a hydrophobic channel in cyt c while the other chain remains in the bilayer.

Apoptosis↗
PubMed2004

Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc.

Zinc is an essential nutrient required for the growth and metabolism of eukaryotic cells. In this work, we examined the effects of zinc depletion on the regulation of phospholipid synthesis in the yeast Saccharomyces cerevisiae. Zinc depletion resulted in a decrease in the activity levels of the CDP-diacylglycerol pathway enzymes phosphatidylserine synthase, phosphatidylserine decarboxylase, phosphatidylethanolamine methyltransferase, and phospholipid methyltransferase. In contrast, the activity of phosphatidylinositol synthase was elevated in response to zinc depletion. The level of Aut7p, a marker for the induction of autophagy, was also elevated in zinc-depleted cells. For the CHO1-encoded phosphatidylserine synthase, the reduction in activity in response to zinc depletion was controlled at the level of transcription. This regulation was mediated through the UAS(INO) element and by the transcription factors Ino2p, Ino4p, and Opi1p that are responsible for the inositol-mediated regulation of UAS(INO)-containing genes involved in phospholipid synthesis. Analysis of the cellular composition of the major membrane phospholipids showed that zinc depletion resulted in a 66% decrease in phosphatidylethanolamine and a 29% increase in phosphatidylinositol. A zrt1Delta zrt2Delta mutant (defective in the plasma membrane zinc transporters Zrt1p and Zrt2p) grown in the presence of zinc exhibited a phospholipid composition similar to that of wild type cells depleted for zinc. These results indicated that a decrease in the cytoplasmic levels of zinc was responsible for the alterations in phospholipid composition.

Autophagy-Related Protein 8 Family↗
PubMed2005

MsbA is not required for phospholipid transport in Neisseria meningitidis.

The outer membrane of Gram-negative bacteria contains phospholipids and lipopolysaccharide (LPS) in the inner and outer leaflet, respectively. Little is known about the transport of the phospholipids from their site of synthesis to the outer membrane. The inner membrane protein MsbA of Escherichia coli, which is involved in the transport of LPS across the inner membrane, has been reported to be involved in phospholipid transport as well. Here, we have reported the construction and the characterization of a Neisseria meningitidis msbA mutant. The mutant was viable, and it showed a retarded growth phenotype and contained very low amounts of LPS. However, it produced an outer membrane, demonstrating that phospholipid transport was not affected by the mutation. Notably, higher amounts of phospholipids were produced in the msbA mutant than in its isogenic parental strain, provided that capsular biosynthesis was also disrupted. Although these results confirmed that MsbA functions in LPS transport, they also demonstrated that it is not required for phospholipid transport, at least not in N. meningitidis.

ATP-Binding Cassette Transporters↗