Novel bioactive glycerol-based lysophospholipids: New data – New insight into their function

Grzelczyk, Anna; Gendaszewska‐Darmach, Edyta

doi:10.1016/j.biochi.2012.10.009

Cited by 140 publications

(126 citation statements)

References 158 publications

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“…A precedent for potential activity of lipid-modifying enzymes in the PV is illustrated by a phosphatidylserine decarboxylase, TgPSD, that is secreted by the parasite into the PV lumen (66). Phosphatidylethanolamine produced by TgPSD is a potent inducer of changes in protein conformation, which influences the lateral movement and activity of membrane-bound proteins (67). Thus, intravacuolar TgPSD1 and TgLCAT may have the potential to regulate the sequestration or processing of host-derived vesicles and lipids by providing an optimal bilayer environment for PV protein functions or liberating host lipids present in vesicles for the parasite (62,64).…”

Section: Discussionmentioning

confidence: 99%

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

Pszenny

Ehrenman

Romano

et al. 2016

Journal of Biological Chemistry

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The protozoan parasite Toxoplasma gondii develops within a parasitophorous vacuole (PV) in mammalian cells, where it scavenges cholesterol. When cholesterol is present in excess in its environment, the parasite expulses this lipid into the PV or esterifies it for storage in lipid bodies. Here, we characterized a unique T. gondii homologue of mammalian lecithin:cholesterol acyltransferase (LCAT), a key enzyme that produces cholesteryl esters via transfer of acyl groups from phospholipids to the 3-OH of free cholesterol, leading to the removal of excess cholesterol from tissues. TgLCAT contains a motif characteristic of serine lipases "AHSLG" and the catalytic triad consisting of serine, aspartate, and histidine (SDH) from LCAT enzymes. TgL-CAT is secreted by the parasite, but unlike other LCAT enzymes it is cleaved into two proteolytic fragments that share the residues of the catalytic triad and need to be reassembled to reconstitute enzymatic activity. TgLCAT uses phosphatidylcholine as substrate to form lysophosphatidylcholine that has the potential to disrupt membranes. The released fatty acid is transferred to cholesterol, but with a lower transesterification activity than mammalian LCAT. TgLCAT is stored in a subpopulation of dense granule secretory organelles, and following secretion, it localizes to the PV and parasite plasma membrane. LCAT-null parasites have impaired growth in vitro, reduced virulence in animals, and exhibit delays in egress from host cells. Parasites overexpressing LCAT show increased virulence and faster egress. These observations demonstrate that TgLCAT influences the outcome of an infection, presumably by facilitating replication and egress depending on the developmental stage of the parasite.The phospholipase A 2 (PLA 2 ) 2 family of serine lipases comprises more than 30 enzymes in mammals. The PLA 2 members hydrolyze the sn-2 ester of phospholipids, yielding lysophospholipid and releasing a fatty acid (1). Approximately one-third of the PLA 2 family members are secreted from cells and display various localizations post-secretion, reflecting their specialized biological functions (2). Among the secretory PLA 2 , lecithin: cholesterol acyltransferase (LCAT; EC 2.3.1.43) is characterized by dual activity, PLA 2 and acyltransferase. In mammals, this enzyme catalyzes the transacylation of the sn-2 fatty acid liberated from various phospholipids (e.g. phosphatidylcholine or phosphatidylethanolamine) to the 3-␤-hydroxyl group on the A-ring of cholesterol, thereby forming cholesteryl esters (3-5). The primary sequence of LCAT is well conserved between mammalian species (6). A structural model for LCAT predicts the conformation of a catalytic triad formed by SerAsp-His residues involved in the phospholipase reaction (7). Mammalian LCATs are primarily expressed in the liver and secreted to the plasma where they circulate in association with HDL (8). These enzymes are components of the reverse cholesterol transport pathway by which cholesterol from peripheral cells is delivered to the liver f...

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Section: Discussionmentioning

confidence: 99%

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

Pszenny

Ehrenman

Romano

et al. 2016

Journal of Biological Chemistry

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“…Lysophospholipids have been observed to induce a wide array of effects in a cell-specific manner. Although many of these effects have been attributed to interaction with surface receptors, a number of receptor-independent effects also have been appreciated: partitioning into the lipid bilayer and altering the properties of cell membranes or directly binding to nonreceptor proteins, such as ion channels (65). The latter are of special relevance for LPE because, unlike other lysophospholipids, specific receptors for LPE have not been described (5).…”

Section: Discussionmentioning

confidence: 99%

“…After the siRNA treatments aimed at blocking sPLA 2 -V expression, the cells, treated or not with IL-4, were exposed to LPE before phagocytosis was measured; LPC and LPI were used as controls. The lysophospholipids were used at 5 mM, a concentration well below their critical micellular concentration, which allows insight into their basic interactions with cell membranes and avoids undesired effects stemming from the formation of vesicles of varying sizes that could interact with the cells in a nonspecific manner (64,65). The data are shown in Fig.…”

Section: Exogenous Lpe Restores Phagocytosis In Spla 2 -V-deficient Cmentioning

confidence: 99%

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Rubio

Rodríguez

Gil-de-Gómez

et al. 2015

The Journal of Immunology

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Studies on the heterogeneity and plasticity of macrophage populations led to the identification of two major polarization states: classically activated macrophages or M1, induced by IFN-γ plus LPS, and alternatively activated macrophages, induced by IL-4. We studied the expression of multiple phospholipase A2 enzymes in human macrophages and the effect that polarization of the cells has on their levels. At least 11 phospholipase A2 genes were found at significant levels in human macrophages, as detected by quantitative PCR. None of these exhibited marked changes after treating the cells with IFN-γ plus LPS. However, macrophage treatment with IL-4 led to strong upregulation of the secreted group V phospholipase A2 (sPLA2-V), both at the mRNA and protein levels. In parallel with increasing sPLA2-V expression levels, IL-4–treated macrophages exhibited increased phagocytosis of yeast-derived zymosan and bacteria, and we show that both events are causally related, because cells deficient in sPLA2-V exhibited decreased phagocytosis, and cells overexpressing the enzyme manifested higher rates of phagocytosis. Mass spectrometry analyses of lipid changes in the IL-4–treated macrophages suggest that ethanolamine lysophospholipid (LPE) is an sPLA2-V–derived product that may be involved in regulating phagocytosis. Cellular levels of LPE are selectively maintained by sPLA2-V. By supplementing sPLA2-V–deficient cells with LPE, phagocytosis of zymosan or bacteria was fully restored in IL-4–treated cells. Collectively, our results show that sPLA2-V is required for efficient phagocytosis by IL-4–treated human macrophages and provide evidence that sPLA2-V–derived LPE is involved in the process.

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“…It is amphiphilic substance with novel bioactive functions 2 . Normally, LPC can be sythesized through the enzymatic hydrolysis of phophatidylcholine PC 3 7 , the esterification of glycerophosphatidyl derivatives 8 13 , and the alcoholysis of PLs catalyzed by lipase 14 16 .…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine Synthesis by Lipase-catalyzed Ethanolysis

Yang

2015

J. Oleo Sci.

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Novel bioactive glycerol-based lysophospholipids: New data – New insight into their function

Cited by 140 publications

References 158 publications

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Lysophosphatidylcholine Synthesis by Lipase-catalyzed Ethanolysis

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