Journal articles: 'Lysobisphosphatidic Acid'

1

Chevallier, Julien, Zeina Chamoun, Guowei Jiang, Glenn Prestwich, Naomi Sakai, Stefan Matile, Robert G. Parton, and Jean Gruenberg. "Lysobisphosphatidic Acid Controls Endosomal Cholesterol Levels." Journal of Biological Chemistry 283, no. 41 (July 21, 2008): 27871–80. http://dx.doi.org/10.1074/jbc.m801463200.

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2

Jiang, Guowei, Yong Xu, Thomas Falguières, Jean Gruenberg, and Glenn D. Prestwich. "Concise Synthesis of Ether Analogues of Lysobisphosphatidic Acid." Organic Letters 7, no. 18 (September 2005): 3837–40. http://dx.doi.org/10.1021/ol051194w.

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Goursot, A., T. Mineva, C. Bissig, J. Gruenberg, and D. R. Salahub. "Structure, Dynamics, and Energetics of Lysobisphosphatidic Acid (LBPA) Isomers." Journal of Physical Chemistry B 114, no. 47 (December 2, 2010): 15712–20. http://dx.doi.org/10.1021/jp108361d.

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Jiang, Guowei, Yong Xu, and Glenn D. Prestwich. "Practical Enantiospecific Syntheses of Lysobisphosphatidic Acid and Its Analogues." Journal of Organic Chemistry 71, no. 3 (February 2006): 934–39. http://dx.doi.org/10.1021/jo051894e.

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Kobayashi, Toshihide, Marie-Hélène Beuchat, Margaret Lindsay, Sonia Frias, Richard D. Palmiter, Hitoshi Sakuraba, Robert G. Parton, and Jean Gruenberg. "Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport." Nature Cell Biology 1, no. 2 (May 15, 1999): 113–18. http://dx.doi.org/10.1038/10084.

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Holopainen, Juha M., Tim Söderlund, Juha-Matti Alakoskela, Matti Säily, Ove Eriksson, and Paavo K. J. Kinnunen. "Intermolecular interactions of lysobisphosphatidic acid with phosphatidylcholine in mixed bilayers." Chemistry and Physics of Lipids 133, no. 1 (January 2005): 51–67. http://dx.doi.org/10.1016/j.chemphyslip.2004.08.004.

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Besson, Nelly, Francoise Hullin-Matsuda, Asami Makino, Motohide Murate, Michel Lagarde, Jean-Francois Pageaux, Toshihide Kobayashi, and Isabelle Delton-Vandenbroucke. "Selective incorporation of docosahexaenoic acid into lysobisphosphatidic acid in cultured THP-1 macrophages." Lipids 41, no. 2 (February 2006): 189–96. http://dx.doi.org/10.1007/s11745-006-5087-5.

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Alessandri, C., M. Bombardieri, L. Di Prospero, P. Conigliaro, F. Conti, G. Labbadia, R. Misasi, M. Sorice, and G. Valesini. "Anti-lysobisphosphatidic acid antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus." Clinical and Experimental Immunology 140, no. 1 (April 2005): 173–80. http://dx.doi.org/10.1111/j.1365-2249.2005.02727.x.

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9

Patel, Avnish, Bjorn-Patrick Mohl, and Polly Roy. "Entry of Bluetongue Virus Capsid Requires the Late Endosome-specific Lipid Lysobisphosphatidic Acid." Journal of Biological Chemistry 291, no. 23 (April 1, 2016): 12408–19. http://dx.doi.org/10.1074/jbc.m115.700856.

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10

Salvioli, Rosa, Massimo Tatti, Susanna Scarpa, Sabrina Maria Moavero, Fiorella Ciaffoni, Federica Felicetti, Christine R. Kaneski, Roscoe O. Brady, and Anna Maria Vaccaro. "The N370S (Asn370→Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C." Biochemical Journal 390, no. 1 (August 9, 2005): 95–103. http://dx.doi.org/10.1042/bj20050325.

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The properties of the endolysosomal enzyme GCase (glucosylceramidase), carrying the most prevalent mutation observed in Gaucher patients, namely substitution of an asparagine residue with a serine at amino acid position 370 [N370S (Asn370→Ser) GCase], were investigated in the present study. We previously demonstrated that Sap (saposin) C, the physiological GCase activator, promotes the association of GCase with anionic phospholipid-containing membranes, reconstituting in this way the enzyme activity. In the present study, we show that, in the presence of Sap C and membranes containing high levels of anionic phospholipids, both normal and N370S GCases are able to associate with the lipid surface and to express their activity. Conversely, when the amount of anionic phospholipids in the membrane is reduced (∼20% of total lipids), Sap C is still able to promote binding and activation of the normal enzyme, but not of N370S GCase. The altered interaction of the mutated enzyme with anionic phospholipid-containing membranes and Sap C was further demonstrated in Gaucher fibroblasts by confocal microscopy, which revealed poor co-localization of N370S GCase with Sap C and lysobisphosphatidic acid, the most abundant anionic phospholipid in endolysosomes. Moreover, we found that N370S Gaucher fibroblasts accumulate endolysosomal free cholesterol, a lipid that might further interfere with the interaction of the enzyme with Sap C and lysobisphosphatidic acid-containing membranes. In summary, our results show that the N370S mutation primarily affects the interaction of GCase with its physiological activators, namely Sap C and anionic phospholipid-containing membranes. We thus propose that the poor contact between N370S GCase and its activators may be responsible for the low activity of the mutant enzyme in vivo.

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Ilnytska, Olga, Maciej Jeziorek, Kimberly Lai, Nihal Altan-Bonnet, Radek Dobrowolski, and Judith Storch. "Lysobisphosphatidic acid (LBPA) enrichment promotes cholesterol egress via exosomes in Niemann Pick type C1 deficient cells." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1866, no. 6 (June 2021): 158916. http://dx.doi.org/10.1016/j.bbalip.2021.158916.

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12

Wang, Shiyu, Hong Sun, Michael Tanowitz, Xue-hai Liang, and Stanley T. Crooke. "Intra-endosomal trafficking mediated by lysobisphosphatidic acid contributes to intracellular release of phosphorothioate-modified antisense oligonucleotides." Nucleic Acids Research 45, no. 9 (April 3, 2017): 5309–22. http://dx.doi.org/10.1093/nar/gkx231.

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13

Castellanos-Castro, Silvia, Sarita Montaño, and Esther Orozco. "Data on docking and dynamics simulation of Entamoeba histolytica EhADH (an ALIX protein) and lysobisphosphatidic acid." Data in Brief 7 (June 2016): 457–59. http://dx.doi.org/10.1016/j.dib.2016.02.067.

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14

Castellanos-Castro, Silvia, Carlos M. Cerda-García-Rojas, Rosario Javier-Reyna, Jonnatan Pais-Morales, Bibiana Chávez-Munguía, and Esther Orozco. "Identification of the phospholipid lysobisphosphatidic acid in the protozoan Entamoeba histolytica : An active molecule in endocytosis." Biochemistry and Biophysics Reports 5 (March 2016): 224–36. http://dx.doi.org/10.1016/j.bbrep.2015.12.010.

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15

HUGHES, William E., and Peter J. PARKER. "Endosomal localization of phospholipase D 1a and 1b is defined by the C-termini of the proteins, and is independent of activity." Biochemical Journal 356, no. 3 (June 8, 2001): 727–36. http://dx.doi.org/10.1042/bj3560727.

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The factors regulating the activity of cellular phospholipase D (PLD) have been well characterized; however, the cellular distribution of specific PLD isoforms and the factors defining localization are less clear. Two specific PLD1 isoforms, PLD1a and PLD1b, are shown in the present study to be localized in endosomal compartments with early endosomal autoantigen 1, internalizing epidermal growth factor receptor (ErbB1) and lysobisphosphatidic acid. Novel C-terminal splice variants of PLD1, PLD1a2 and PLD1b2, do not exhibit this endosomal localization. Studies using catalytically inactive and C-terminal deletion mutants of the four PLD1 isoforms led to the conclusion that the C-terminus plays an important part in the catalytic activity of PLD1, but that the endosomal localization of PLD1a and PLD1b is defined by the C-terminus and not catalytic activity.

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16

Prestwich, G. D., Y. Xu, L. Qian, J. Gajewiak, and G. Jiang. "New metabolically stabilized analogues of lysophosphatidic acid: agonists, antagonists and enzyme inhibitors." Biochemical Society Transactions 33, no. 6 (October 26, 2005): 1357–61. http://dx.doi.org/10.1042/bst0331357.

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Lysophosphatidic acid (LPA) is a metabolically labile natural phospholipid with a bewildering array of physiological effects. We describe herein a variety of long-lived receptor-specific agonists and antagonists for LPA receptors. Several LPA and PA (phosphatidic acid) analogues also inhibit LPP (lipid phosphate phosphatase). The sn-1 or sn-2 hydroxy groups have been replaced by fluorine, difluoromethyl, difluoroethyl, O-methyl or O-hydroxyethoxy groups to give non-migrating LPA analogues that resist acyltransferases. Alkyl ether replacement of acyl esters produced lipase and acyltransferase-resistant analogues. Replacement of the bridging oxygen in the monophosphate by an α-monofluoromethylene-, α-bromomethylene- or α,α-difluoromethylenephosphonate gave phosphatase-resistant analogues. Phosphorothioate analogues with O-acyl and O-alkyl chains are potent, long-lived agonists for LPA1 and LPA3 receptors. Most recently, we have (i) prepared stabilized O-alkyl analogues of lysobisphosphatidic acid, (ii) explored the structure–activity relationship of stabilized cyclic LPA analogues and (iii) synthesized neutral head group trifluoromethylsulphonamide analogues of LPA. Through collaborative studies, we have collected data for these stabilized analogues as selective LPA receptor (ant)agonists, LPP inhibitors, TREK (transmembrane calcium channel) K+ channel agonists, activators of the nuclear transcription factor PPAR-γ (peroxisome-proliferator-activated receptor-γ), promoters of cell motility and survival, and radioprotectants for human B-cells.

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17

Reaves, B. J., P. E. Row, N. A. Bright, J. P. Luzio, and H. W. Davidson. "Loss of cation-independent mannose 6-phosphate receptor expression promotes the accumulation of lysobisphosphatidic acid in multilamellar bodies." Journal of Cell Science 113, no. 22 (November 15, 2000): 4099–108. http://dx.doi.org/10.1242/jcs.113.22.4099.

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A number of recent studies have highlighted the importance of lipid domains within endocytic organelles in the sorting and movement of integral membrane proteins. In particular, considerable attention has become focussed upon the role of the unusual phospholipid lysobisphosphatidic acid (LBPA). This lipid appears to be directly involved in the trafficking of cholesterol and glycosphingolipids, and accumulates in a number of lysosomal storage disorders. Antibody-mediated disruption of LBPA function also leads to mis-sorting of cation-independent mannose 6-phosphate receptors. We now report that the converse is also true, and that spontaneous loss of cation-independent mannose 6-phosphate receptors from a rat fibroblast cell line led to the formation of aberrant late endocytic structures enriched in LBPA. Accumulation of LBPA was directly dependent upon the loss of the receptors, and could be reversed by expression of bovine cation-independent mannose 6-phosphate receptors in the mutant cell line. Ultrastructural analysis indicated that the abnormal organelles were electron-dense, had a multi-lamellar structure, accumulated endocytosed probes, and were distinct from dense-core lysosomes present within the same cells. The late endocytic structures present at steady state within any particular cell likely reflect the balance of membrane traffic through the endocytic pathway of that cell, and the rate of maturation of individual endocytic organelles. Moreover, there is considerable evidence which suggests that cargo receptors also play a direct mechanistic role in membrane trafficking events. Therefore, loss of such a protein may disturb the overall equilibrium of the pathway, and hence cause the accumulation of aberrant organelles. We propose that this mechanism underlies the phenotype of the mutant cell line, and that the formation of inclusion bodies in many lysosomal storage diseases is also due to an imbalance in membrane trafficking within the endocytic pathway.

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18

Pattanakitsakul, Sa-nga, Jesdaporn Poungsawai, Rattiyaporn Kanlaya, Supachok Sinchaikul, Shui-Tein Chen, and Visith Thongboonkerd. "Association of Alix with Late Endosomal Lysobisphosphatidic Acid Is Important for Dengue Virus Infection in Human Endothelial Cells." Journal of Proteome Research 9, no. 9 (September 3, 2010): 4640–48. http://dx.doi.org/10.1021/pr100357f.

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19

Lee, Sangderk, and Kevin R. Lynch. "Brown recluse spider (Loxosceles reclusa) venom phospholipase D (PLD) generates lysophosphatidic acid (LPA)." Biochemical Journal 391, no. 2 (October 10, 2005): 317–23. http://dx.doi.org/10.1042/bj20050043.

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Envenomation by the brown recluse spider (Loxosceles reclusa) may cause local dermonecrosis and, rarely, coagulopathies, kidney failure and death. A venom phospholipase, SMaseD (sphingomyelinase D), is responsible for the pathological manifestations of envenomation. Recently, the recombinant SMaseD from Loxosceles laeta was demonstrated to hydrolyse LPC (lysophosphatidylcholine) to produce LPA (lysophosphatidic acid) and choline. Therefore activation of LPA signalling pathways may be involved in some manifestations of Loxosceles envenomation. To begin investigating this idea, we cloned a full-length cDNA encoding L. reclusa SMaseD. The 305 amino acid sequence of the L. reclusa enzyme is 87, 85 and 60% identical with those of L. arizonica, L. intermedia and L. laeta respectively. The recombinant enzyme expressed in bacteria had broad substrate specificity. The lysophospholipids LPC, LPI (18:1-1-oleyol lysophosphatidylinositol), LPS, LPG (18:1-1-oleoyl-lysophosphatidylglycerol), LBPA (18:1-1-oleoyl-lysobisphosphatidic acid) (all with various acyl chains), lyso-platelet-activating factor (C16:0), cyclic phosphatidic acid and sphingomyelin were hydrolysed, whereas sphingosylphosphorylcholine, PC (phosphatidylcholine; C22:6, C20:4 and C6:0), oxidized PCs and PAF (platelet-activating factor; C16:0) were not hydrolysed. The PAF analogue, edelfosine, inhibited enzyme activity. Recombinant enzyme plus LPC (C18:1) induced the migration of A2058 melanoma cells, and this activity was blocked by the LPA receptor antagonist, VPC32183. The recombinant spider enzyme was haemolytic, but this activity was absent from catalytically inactive H37N (His37→Asn) and H73N mutants. Our results demonstrate that Loxosceles phospholipase D hydrolyses a wider range of lysophospholipids than previously supposed, and thus the term ‘SMaseD’ is too limited in describing this enzyme.

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Hussein, Mohammed A., Heba M. Abo-Salem, Ahmed M. Moro, Ebtsam A. Abdel-Wahab, Ali A. Ali, and Shaimaa A. Abdelkawy. "Pulmonary Phospholipid Components as Promising Natural Inhibitors against COVID-19 Mpro; Molecular Docking Analysis Based Study." Asian Journal of Chemistry 34, no. 9 (2022): 2191–97. http://dx.doi.org/10.14233/ajchem.2022.23691.

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The ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome SARS-CoV-2 has become a global crisis. Phospholipids are structural components of mammalian cell membranes that suppress viral attachment to the plasma membrane and subsequent replication in lung cells. Using the molecular docking approach, the inhibitory activity of phosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, lysobisphosphatidic acid and sphingomyelin against SARS CoV-2 by targeting main protease (Mpro, PDB code: 6LU7) has been investigated. All phospholipids established excellent binding to Mpro active bocket by forming several H-bonds with the catalytic amino acids Cys145 and His4, as well as various amino acids involved in the bocket. Furthermore, a potent binding affinity is increased from -7.01 to -9.16 kcal/mol compared to compound N3 (N-[(5-methylisoxazol-3-yl)carbonyl]alanyl- L (where L = valyl-N-1-(1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2- enyl)-L-leucinamide), a peptide linker, inhibitor for Covid-19 main protease. Co-crystalline ligand of enzyme 6LU7 of -9.99 kcal/mol. The sphingomyelin has the same binding affinity to main protease when compared to compound N3. These findings implied that the selected compounds have the potential to be developed as novel SARS-CoV-2 inhibitors. Therefore, improved, well-designed, potent and structurally and pharmacokinetically effective drugs are urgently needed. Further investigations should focus on validating and finalizing effective drugs for COVID-19 beyond preliminary in silico and in vivo screening.

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21

Schaible, U. E., P. H. Schlesinger, T. H. Steinberg, W. F. Mangel, T. Kobayashi, and D. G. Russell. "Parasitophorous vacuoles of Leishmania mexicana acquire macromolecules from the host cell cytosol via two independent routes." Journal of Cell Science 112, no. 5 (March 1, 1999): 681–93. http://dx.doi.org/10.1242/jcs.112.5.681.

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The intracellular parasite Leishmania survives and proliferates in host macrophages. In this study we show that parasitophorous vacuoles of L. mexicana gain access to cytosolic material via two different routes. (1) Small anionic molecules such as Lucifer Yellow are rapidly transported into the vacuoles by an active transport mechanism that is sensitive to inhibitors of the host cell's organic anion transporter. (2) Larger molecules such as fluorescent dextrans introduced into the host cell cytosol are also delivered to parasitophorous vacuoles. This transport is slower and sensitive to modulators of autophagy. Infected macrophages were examined by two novel assays to visualize and quantify this process. Immunoelectron microscopy of cells loaded with digoxigenin-dextran revealed label in multivesicular endosomes, which appeared to fuse with parasitophorous vacuoles. The inner membranes of the multivesicular vesicles label strongly with antibodies against lysobisphosphatidic acid, suggesting that they represent a point of confluence between the endosomal and autophagosomal pathways. Although the rate of autophagous transfer was comparable in infected and uninfected cells, infected cells retained hydrolyzed cysteine proteinase substrate to a greater degree. These data suggest that L. mexicana-containing vacuoles have access to potential nutrients in the host cell cytosol via at least two independent mechanisms.

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22

Hartwig, Pia, and Doris Höglinger. "The Glucosylceramide Synthase Inhibitor PDMP Causes Lysosomal Lipid Accumulation and mTOR Inactivation." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7065. http://dx.doi.org/10.3390/ijms22137065.

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For many years, the biology of glycosphingolipids was elucidated with the help of glucosylceramide synthase (GCS) inhibitors such as 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Additionally, PDMP gained interest because of its chemosensitizing effects. Several studies have successfully combined PDMP and anti-cancer drugs in the context of cancer therapy. However, the mechanism of action of PDMP is not fully understood and seems to go beyond glycolipid inhibition. Here, we used a functionalized sphingosine analogue (pacSph) to investigate the acute effects of PDMP on cellular sphingolipid distribution and found that PDMP, but not other GCS inhibitors, such as ND-DNJ (also called Miglustat), induced sphingolipid accumulation in lysosomes. This effect could be connected to defective export from lysosome, as monitored by the prolonged lysosomal staining of sphingolipids as well as by a delay in the metabolic conversion of the pacSph precursor. Additionally, other lipids such as lysobisphosphatidic acid (LBPA) and cholesterol were enriched in lysosomes upon PDMP treatment in a time-dependent manner. We could further correlate early LBPA enrichment with dissociation of the mechanistic target of rapamycin (mTOR) from lysosomes followed by nuclear translocation of its downtream target, transcription factor EB (TFEB). Altogether, we report here a timeline of lysosomal lipid accumulation events and mTOR inactivation arising from PDMP treatment.

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23

Kobayashi, Toshihide, Ulrich M. Vischer, Corinne Rosnoblet, Cécile Lebrand, Margaret Lindsay, Robert G. Parton, Egbert K. O. Kruithof, and Jean Gruenberg. "The Tetraspanin CD63/lamp3 Cycles between Endocytic and Secretory Compartments in Human Endothelial Cells." Molecular Biology of the Cell 11, no. 5 (May 2000): 1829–43. http://dx.doi.org/10.1091/mbc.11.5.1829.

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In the present study, we show that in human endothelial cells the tetraspanin CD63/lamp3 distributes predominantly to the internal membranes of multivesicular–multilamellar late endosomes, which contain the unique lipid lysobisphosphatidic acid. Some CD63/lamp3 is also present in Weibel–Palade bodies, the characteristic secretory organelle of these cells. We find that CD63/lamp3 molecules can be transported from late endosomes to Weibel–Palade bodies and thus that CD63/lamp3 cycles between endocytic and biosynthetic compartments; however, movement of CD63/lamp3 is much slower than that of P-selectin, which is known to cycle between plasma membrane and Weibel–Palade bodies. When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel–Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes. Our data suggest that CD63/lamp3 partitions preferentially within late endosome internal membranes, thus causing its accumulation, and that this mechanism contributes to CD63/lamp3 retention in late endosomes; however, our data also indicate that the protein can eventually escape from these internal membranes and recycle toward Weibel–Palade bodies to be reused. Our observations thus uncover the existence of a selective trafficking route from late endosomes to Weibel–Palade bodies.

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24

Vieira, Otilia V., Rene E. Harrison, Cameron C. Scott, Harald Stenmark, David Alexander, Jun Liu, Jean Gruenberg, Alan D. Schreiber, and Sergio Grinstein. "Acquisition of Hrs, an Essential Component of Phagosomal Maturation, Is Impaired by Mycobacteria." Molecular and Cellular Biology 24, no. 10 (May 15, 2004): 4593–604. http://dx.doi.org/10.1128/mcb.24.10.4593-4604.2004.

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ABSTRACT Pathogenic mycobacteria survive within macrophages by precluding the fusion of phagosomes with late endosomes or lysosomes. Because the molecular determinants of normal phagolysosome formation are poorly understood, the sites targeted by mycobacteria remain unidentified. We found that Hrs, an adaptor molecule involved in protein sorting, associates with phagosomes prior to their fusion with late endosomes or lysosomes. Recruitment of Hrs required the interaction of its FYVE domain with phagosomal phosphatidylinositol 3-phosphate, but two other attachment sites were additionally involved. Depletion of Hrs by use of small interfering RNA impaired phagosomal maturation, preventing the acquisition of lysobisphosphatidic acid and reducing luminal acidification. As a result, the maturation of phagosomes formed in Hrs-depleted cells was arrested at an early stage, characterized by the acquisition and retention of sorting endosomal markers. This phenotype is strikingly similar to that reported to occur in phagosomes of cells infected by mycobacteria. We therefore tested whether Hrs is recruited to phagosomes containing mycobacteria. Hrs associated readily with phagosomes containing inert particles but poorly with mycobacterial phagosomes. Moreover, Hrs was found more frequently in phagosomes containing avirulent Mycobacterium smegmatis than in phagosomes with the more virulent Mycobacterium marinum. These findings suggest that the inability to recruit Hrs contributes to the arrest of phagosomal maturation induced by pathogenic mycobacteria.

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Conti, Fabrizio, Antonella Capozzi, Simona Truglia, Emanuela Lococo, Agostina Longo, Roberta Misasi, Cristiano Alessandri, Guido Valesini, and Maurizio Sorice. "The Mosaic of “Seronegative” Antiphospholipid Syndrome." Journal of Immunology Research 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/389601.

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In the clinical practice it is possible to find patients with clinical signs suggestive of antiphospholipid syndrome (APS), who are persistently negative for the laboratory criteria of APS, that is, anti-cardiolipin antibodies (aCL), anti-β2-GPI antibodies and lupus anticoagulant. Therefore, it was proposed for these cases the term of seronegative APS (SN-APS). In order to detect autoantibodies with different methodological approaches, sera from 24 patients with SN-APS were analysed for anti-phospholipid antibodies using TLC immunostaining, for anti-vimentin/cardiolipin antibodies by enzyme-linked immunosorbent assay (ELISA), and for anti-annexin V and anti-prothrombin antibodies by ELISA and dot blot. Control groups of our study were 25 patients with APS, 18 with systemic lupus erythematosus (SLE), and 32 healthy controls. Results revealed that 13/24 (54.2%) SN-APS sera were positive for aCL (9 of whom were also positive for lysobisphosphatidic acid) by TLC immunostaining, 11/24 (45.8%) for anti-vimentin/cardiolipin antibodies, 3/24 (12.5%) for anti-prothrombin antibodies, and 1/24 (4.2%) for anti-annexin V antibodies. These findings suggest that in sera from patients with SN-APS, antibodies may be detected using “new” antigenic targets (mainly vimentin/cardiolipin) or methodological approaches different from traditional techniques (mainly TLC immunostaining). Thus, SN-APS represents a mosaic, in which antibodies against different antigenic targets may be detected.

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Grabner, Gernot F., Nermeen Fawzy, Renate Schreiber, Lisa M. Pusch, Dominik Bulfon, Harald Koefeler, Thomas O. Eichmann, et al. "Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice." Journal of Lipid Research 61, no. 7 (April 29, 2020): 995–1003. http://dx.doi.org/10.1194/jlr.ra119000516.

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Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid, is a phospholipid that promotes lipid sorting in late endosomes/lysosomes by activating lipid hydrolases and lipid transfer proteins. Changes in the cellular BMP content therefore reflect an altered metabolic activity of the endolysosomal system. Surprisingly, little is known about the physiological regulation of BMP. In this study, we investigated the effects of nutritional and metabolic factors on BMP profiles of whole tissues and parenchymal and nonparenchymal cells. Tissue samples were obtained from fed, fasted, 2 h refed, and insulin-treated mice, as well as from mice housed at 5°C, 22°C, or 30°C. These tissues exhibited distinct BMP profiles that were regulated by the nutritional state in a tissue-specific manner. Insulin treatment was not sufficient to mimic refeeding-induced changes in tissue BMP levels, indicating that BMP metabolism is regulated by other hormonal or nutritional factors. Tissue fractionation experiments revealed that fasting drastically elevates BMP levels in hepatocytes and pancreatic cells. Furthermore, we observed that the BMP content in brown adipose tissue strongly depends on housing temperatures. In conclusion, our observations suggest that BMP concentrations adapt to the metabolic state in a tissue- and cell-type-specific manner in mice. Drastic changes observed in hepatocytes, pancreatic cells, and brown adipocytes suggest that BMP plays a role in the functional adaption to nutrient starvation and ambient temperature.

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Kufareva, Irina, Marc Lenoir, Felician Dancea, Pooja Sridhar, Eugene Raush, Christin Bissig, Jean Gruenberg, Ruben Abagyan, and Michael Overduin. "Discovery of novel membrane binding structures and functions." Biochemistry and Cell Biology 92, no. 6 (December 2014): 555–63. http://dx.doi.org/10.1139/bcb-2014-0074.

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The function of a protein is determined by its intrinsic activity in the context of its subcellular distribution. Membranes localize proteins within cellular compartments and govern their specific activities. Discovering such membrane-protein interactions is important for understanding biological mechanisms and could uncover novel sites for therapeutic intervention. We present a method for detecting membrane interactive proteins and their exposed residues that insert into lipid bilayers. Although the development process involved analysis of how C1b, C2, ENTH, FYVE, Gla, pleckstrin homology (PH), and PX domains bind membranes, the resulting membrane optimal docking area (MODA) method yields predictions for a given protein of known three-dimensional structures without referring to canonical membrane-targeting modules. This approach was tested on the Arf1 GTPase, ATF2 acetyltransferase, von Willebrand factor A3 domain, and Neisseria gonorrhoeae MsrB protein and further refined with membrane interactive and non-interactive FAPP1 and PKD1 pleckstrin homology domains, respectively. Furthermore we demonstrate how this tool can be used to discover unprecedented membrane binding functions as illustrated by the Bro1 domain of Alix, which was revealed to recognize lysobisphosphatidic acid (LBPA). Validation of novel membrane-protein interactions relies on other techniques such as nuclear magnetic resonance spectroscopy (NMR), which was used here to map the sites of micelle interaction. Together this indicates that genome-wide identification of known and novel membrane interactive proteins and sites is now feasible and provides a new tool for functional annotation of the proteome.

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CIAFFONI, Fiorella, Massimo TATTI, Rosa SALVIOLI, and Anna Maria VACCARO. "Interaction of saposin D with membranes: effect of anionic phospholipids and sphingolipids." Biochemical Journal 373, no. 3 (August 1, 2003): 785–92. http://dx.doi.org/10.1042/bj20030359.

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Saposin (Sap) D is an endolysosomal protein that, together with three other similar proteins, Sap A, Sap B and Sap C, is involved in the degradation of sphingolipids and, possibly, in the solubilization and transport of gangliosides. We found that Sap D is able to destabilize and disrupt membranes containing each of the three anionic phospholipids most abundant in the acidic endolysosomal compartment, namely lysobisphosphatidic acid (LBPA), phosphatidylinositol (PI) and phosphatidylserine (PS). The breakdown of the membranes, which occurs when the Sap D concentration on the lipid surface reaches a critical value, is a slow process that gives rise to small particles. The Sap D–particle complexes formed in an acidic milieu can be dissociated by an increase in pH, suggesting a dynamic association of Sap D with membranes. The presence of anionic phospholipids is required also for the Sap D-induced perturbation and solubilization of membranes containing a neutral sphingolipid such as ceramide or a ganglioside such as GM1. At appropriate Sap D concentrations Cer and GM1 are solubilized as constituents of small phospholipid particles. Our findings imply that most functions of Sap D are dependent on its interaction with anionic phospholipids, which mediate the Sap D effect on other components of the membrane such as sphingolipids. On consideration of the properties of Sap D we propose that Sap D might have a role in the definition of the structure and function of membranes, such as the intra-endolysosomal membranes, that are rich in anionic phospholipids.

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Alcon-LePoder, Sophie, Marie-Thérèse Drouet, Pascal Roux, Marie-Pascale Frenkiel, Michel Arborio, Anne-Marie Durand-Schneider, Michèle Maurice, Isabelle Le Blanc, Jean Gruenberg, and Marie Flamand. "The Secreted Form of Dengue Virus Nonstructural Protein NS1 Is Endocytosed by Hepatocytes and Accumulates in Late Endosomes: Implications for Viral Infectivity." Journal of Virology 79, no. 17 (September 1, 2005): 11403–11. http://dx.doi.org/10.1128/jvi.79.17.11403-11411.2005.

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ABSTRACT The flavivirus nonstructural protein NS1 is expressed as three discrete species in infected mammalian cells: an intracellular, membrane-associated form essential for viral replication, a cell surface-associated form that may be involved in signal transduction, and a secreted form (sNS1), the biological properties of which remain elusive. To determine the distribution of the dengue virus (DEN) sNS1 protein in vivo, we have analyzed by immunohistological means the tissue tropism of purified DEN sNS1 injected intravenously into adult mice. The sNS1 protein was found predominantly associated with the liver, where hepatocytes appeared to represent a major target cell. We further showed that sNS1 could be efficiently endocytosed by human Huh7 and HepG2 hepatocytes in vitro. After its internalization, the protein was detected intracellularly for at least 48 h without being substantially degraded. Colocalization studies of sNS1 with markers of the endolysosomal compartments revealed that the protein was specifically targeted to lysobisphosphatidic acid-rich structures reminiscent of late endosomes, as confirmed by electron microscopy. Intracellular accumulation of sNS1 in Huh7 cells enhanced the fluid phase uptake of rhodamine-labeled dextran. Furthermore, preincubation of Huh7 cells with sNS1 increased dengue virus production after infection with the homologous strain of DEN-1 virus. Our results demonstrate that the accumulation of DEN sNS1 in the late endosomal compartment of hepatocytes potentializes subsequent dengue virus infection in vitro, raising the possibility that sNS1 may contribute to viral propagation in vivo.

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Tomaš, Maja Ilić, Natalia Kučić, Hana Mahmutefendić, Gordana Blagojević, and Pero Lučin. "Murine Cytomegalovirus Perturbs Endosomal Trafficking of Major Histocompatibility Complex Class I Molecules in the Early Phase of Infection." Journal of Virology 84, no. 21 (August 18, 2010): 11101–12. http://dx.doi.org/10.1128/jvi.00988-10.

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ABSTRACT Murine cytomegalovirus (MCMV) functions interfere with protein trafficking in the secretory pathway. In this report we used Δm138-MCMV, a recombinant virus with a deleted viral Fc receptor, to demonstrate that MCMV also perturbs endosomal trafficking in the early phase of infection. This perturbation had a striking impact on cell surface-resident major histocompatibility complex class I (MHC-I) molecules due to the complementary effect of MCMV immunoevasins, which block their egress from the secretory pathway. In infected cells, constitutively endocytosed cell surface-resident MHC-I molecules were arrested and retained in early endosomal antigen 1 (EEA1)-positive and lysobisphosphatidic acid (LBPA)-negative perinuclear endosomes together with clathrin-dependent cargo (transferrin receptor, Lamp1, and epidermal growth factor receptor). Their progression from these endosomes into recycling and degradative routes was inhibited. This arrest was associated with a reduction of the intracellular content of Rab7 and Rab11, small GTPases that are essential for the maturation of recycling and endolysosomal domains of early endosomes. The reduced recycling of MHC-I in Δm138-MCMV-infected cells was accompanied by their accelerated loss from the cell surface. The MCMV function that affects cell surface-resident MHC-I was activated in later stages of the early phase of viral replication, after the expression of known immunoevasins. MCMV without the three immunoevasins (the m04, m06, and m152 proteins) encoded a function that affects endosomal trafficking. This function, however, was not sufficient to reduce the cell surface expression of MHC-I in the absence of the transport block in the secretory pathway.

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YORIKAWA, Chiharu, Hideki SHIBATA, Satoshi WAGURI, Kazumi HATTA, Mio HORII, Keiichi KATOH, Toshihide KOBAYASHI, Yasuo UCHIYAMA, and Masatoshi MAKI. "Human CHMP6, a myristoylated ESCRT-III protein, interacts directly with an ESCRT-II component EAP20 and regulates endosomal cargo sorting." Biochemical Journal 387, no. 1 (March 22, 2005): 17–26. http://dx.doi.org/10.1042/bj20041227.

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CHMP6 (charged multivesicular body protein 6) is a human orthologue of yeast Vps (vacuolar protein sorting) 20, a component of ESCRT (endosomal sorting complex required for transport)-III. Various CHMP6 orthologues in organisms ranging from yeast to humans contain the N-myristoylation consensus sequence at each N-terminus. Metabolic labelling of HEK-293 (human embryonic kidney) cells showed the incorporation of [3H]myristate into CHMP6 fused C-terminally to GFP (green fluorescent protein) (CHMP6–GFP). Interactions of CHMP6 with another ESCRT-III component CHMP4b/Shax [Snf7 (sucrose non-fermenting 7) homologue associated with Alix] 1, one of three paralogues of human Vps32/Snf7, and with EAP20 (ELL-associated protein 20), a human counterpart of yeast Vps25 and component of ESCRT-II, were observed by co-immunoprecipitation of epitope-tagged proteins expressed in HEK-293 cells. The in vitro pull-down assays using their recombinant proteins purified from Escherichia coli demonstrated direct physical interactions which were mediated by the N-terminal basic half of CHMP6. Overexpressed CHMP6-GFP in HeLa cells exhibited a punctate distribution throughout the cytoplasm especially in the perinuclear area, as revealed by fluorescence microscopic analysis. Accumulation of LBPA (lysobisphosphatidic acid), a major phospholipid in internal vesicles of an MVB (multivesicular body), was observed in the CHMP6–GFP-localizing area. FLAG-tagged EAP20 distributed diffusely, but exhibited a punctate distribution on co-expression with CHMP6–GFP. Overexpression of CHMP6–GFP caused reduction of transferrin receptors on the plasma membrane surface, but caused their accumulation in the cytoplasm. Ubiquitinated proteins and endocytosed EGF continuously accumulated in CHMP6–GFP-expressing cells. These results suggest that CHMP6 acts as an acceptor for ESCRT-II on endosomal membranes and regulates cargo sorting.

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Chevallier, Julien, Naomi Sakai, Fabien Robert, Toshihide Kobayashi, Jean Gruenberg, and Stefan Matile. "Rapid Access to Synthetic Lysobisphosphatidic Acids Using PIIIChemistry." Organic Letters 2, no. 13 (June 2000): 1859–61. http://dx.doi.org/10.1021/ol0059246.

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Chinthapally, Kiran, Brian S. J. Blagg, and Brandon L. Ashfeld. "Syntheses of Symmetrical and Unsymmetrical Lysobisphosphatidic Acid Derivatives." Journal of Organic Chemistry, July 27, 2022. http://dx.doi.org/10.1021/acs.joc.2c01176.

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Kobayashi, Toshihide, Konstantin Startchev, Andrew J. Whitney, and Jean Gruenberg. "Localization of Lysobisphosphatidic Acid-Rich Membrane Domains in Late Endosomes." Biological Chemistry 382, no. 3 (January 21, 2001). http://dx.doi.org/10.1515/bc.2001.059.

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McCauliff, Leslie A., Annette Langan, Ran Li, Olga Ilnytska, Debosreeta Bose, Miriam Waghalter, Kimberly Lai, Peter C. Kahn, and Judith Storch. "Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid." eLife 8 (October 3, 2019). http://dx.doi.org/10.7554/elife.50832.

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Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (PG), is entirely ineffective, indicating an obligate functional interaction between NPC2 and LBPA in cholesterol trafficking. We further demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Together these studies reveal a heretofore unknown step of intracellular cholesterol trafficking which is critically dependent upon the interaction of LBPA with functional NPC2 protein.

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Olivieri, S., A. Ruffatti, A. Bontadi, A. Cavazzana, E. Salvan, S. Cuffaro, S. Giunco, and L. Punzi. "Clinical value of antibodies to lysobisphosphatidic acid in patients with primary antiphospholipid sindrome." Reumatismo 62, no. 2 (June 24, 2011). http://dx.doi.org/10.4081/reumatismo.2010.107.

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Jabs, Sabrina, Reijo Käkelä, Arne Quitsch, Jaana Tyynelä, Helmut Brade, Markus Glatzel, Paul Saftig, Marie Vanier, and Thomas Braulke. "Neuronal accumulation of lysobisphosphatidic acid in mice deficient for the lysosomal protease cathepsin D." GBM Annual Spring meeting Mosbach 2007 2007, Spring (March 2007). http://dx.doi.org/10.1240/sav_gbm_2007_m_001724.

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Moreau, Dimitri, Fabrizio Vacca, Stefania Vossio, Cameron Scott, Alexandria Colaco, Jonathan Paz Montoya, Charles Ferguson, et al. "Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice." EMBO reports 20, no. 7 (May 22, 2019). http://dx.doi.org/10.15252/embr.201847055.

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Larios, Jorge, Vincent Mercier, Aurélien Roux, and Jean Gruenberg. "ALIX- and ESCRT-III–dependent sorting of tetraspanins to exosomes." Journal of Cell Biology 219, no. 3 (February 12, 2020). http://dx.doi.org/10.1083/jcb.201904113.

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The intraluminal vesicles (ILVs) of endosomes mediate the delivery of activated signaling receptors and other proteins to lysosomes for degradation, but they also modulate intercellular communication when secreted as exosomes. The formation of ILVs requires four complexes, ESCRT-0, -I, -II, and -III, with ESCRT-0, -I, and -II presumably involved in cargo sorting and ESCRT-III in membrane deformation and fission. Here, we report that an active form of the ESCRT-associated protein ALIX efficiently recruits ESCRT-III proteins to endosomes. This recruitment occurs independently of other ESCRTs but requires lysobisphosphatidic acid (LBPA) in vivo, and can be reconstituted on supported bilayers in vitro. Our data indicate that this ALIX- and ESCRT-III–dependent pathway promotes the sorting and delivery of tetraspanins to exosomes. We conclude that ALIX provides an additional pathway of ILV formation, secondary to the canonical pathway, and that this pathway controls the targeting of exosomal proteins.

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Kapustin, Alexander N., Paul Davey, David Longmire, Carl Matthews, Emily Linnane, Nitin Rustogi, Maria Stavrou, et al. "Antisense oligonucleotide activity in tumour cells is influenced by intracellular LBPA distribution and extracellular vesicle recycling." Communications Biology 4, no. 1 (November 1, 2021). http://dx.doi.org/10.1038/s42003-021-02772-0.

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AbstractNext generation modified antisense oligonucleotides (ASOs) are commercially approved new therapeutic modalities, yet poor productive uptake and endosomal entrapment in tumour cells limit their broad application. Here we compare intracellular traffic of anti KRAS antisense oligonucleotide (AZD4785) in tumour cell lines PC9 and LK2, with good and poor productive uptake, respectively. We find that the majority of AZD4785 is rapidly delivered to CD63+late endosomes (LE) in both cell lines. Importantly, lysobisphosphatidic acid (LBPA) that triggers ASO LE escape is presented in CD63+LE in PC9 but not in LK2 cells. Moreover, both cell lines recycle AZD4785 in extracellular vesicles (EVs); however, AZD4785 quantification by advanced mass spectrometry and proteomic analysis reveals that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhances AZD4785 activity in LK2 but not in PC9 cells thus offering a possible strategy to enhance ASO potency in tumour cells with poor productive uptake of ASOs.

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Galindo, Ausencio, Rosario Javier-Reyna, Guillermina García-Rivera, Cecilia Bañuelos, Sarita Montaño, Jaime Ortega-Lopez, Bibiana Chávez-Munguía, Lizbeth Salazar-Villatoro, and Esther Orozco. "EhVps23: A Component of ESCRT-I That Participates in Vesicular Trafficking and Phagocytosis of Entamoeba histolytica." Frontiers in Cellular and Infection Microbiology 11 (October 29, 2021). http://dx.doi.org/10.3389/fcimb.2021.770759.

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The endosomal sorting complex required for transport (ESCRT) is formed by ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III complexes, and accessory proteins. It conducts vesicular trafficking in eukaryotes through the formation of vesicles and membrane fission and fusion events. The trophozoites of Entamoeba histolytica, the protozoan responsible for human amoebiasis, presents an active membrane movement in basal state that increases during phagocytosis and tissue invasion. ESCRT-III complex has a pivotal role during these events, but ESCRT-0, ESCRT-I and ESCRT-II have been poorly studied. Here, we unveiled the E. histolytica ESCRT-I complex and its implication in vesicular trafficking and phagocytosis, as well as the molecular relationships with other phagocytosis-involved molecules. We found a gene encoding for a putative EhVps23 protein with the ubiquitin-binding and Vps23 core domains. In basal state, it was in the plasma membrane, cytoplasmic vesicles and multivesicular bodies, whereas during phagocytosis it was extensively ubiquitinated and detected in phagosomes and connected vesicles. Docking analysis, immunoprecipitation assays and microscopy studies evidenced its interaction with EhUbiquitin, EhADH, EhVps32 proteins, and the lysobisphosphatidic acid phospholipid. The knocking down of the Ehvps23 gene resulted in lower rates of phagocytosis. Our results disclosed the concert of finely regulated molecules and vesicular structures participating in vesicular trafficking-related events with a pivotal role of EhVps23.

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Allada, Tamara, Olga Ilnytska, and Judith Storch. "Role of Autophagy in Phosphatidyl- Glycerol Facilitated Cholesterol Clearance from the Endolysosomal System of Npc-1 Deficient Cells." Aresty Rutgers Undergraduate Research Journal 1, no. 3 (October 7, 2021). http://dx.doi.org/10.14713/arestyrurj.v1i3.171.

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Niemann Pick Type C (NPC) Disease is a rare lysosomal storage disorder in which one of the genes that codes for either the NPC-1 or NPC-2 pro-tein is mutated, causing cell lysosomes to accumu-late cholesterol and lipids. Previous studies discov-ered that a unique late endosomal/lysosomal phos-pholipid, lysobisphosphatidic acid (LPBA), is in-volved in cholesterol clearance from late endo-somes. It has also been shown that exogenous treat-ment of the NPC-1 deficient cells with LBPA’s precur-sor, phosphatidylglycerol (PG), leads to LBPA enrich-ment and subsequent endolysosomal cholesterol clearance. Autophagy is a mechanism of cellular clearance in the endolysomal system and we are in-terested to see if it is a partial route in cholesterol clearance during PG treatment of NPC-1 deficient cells. To do so, we silenced the gene that codes for an essential protein in the autophagy pathway, mak-ing the cells autophagy deficient. We then treated the cells with PG, measured the amount of choles-terol clearance in those cells, and compared it to cells with normal autophagy. We found significantly less cholesterol clearance by PG in cells with defec-tive autophagy, confirming that autophagy is in-volved as a partial route in cholesterol clearance dur-ing PG treatment, but not enough of a difference to conclude that it is a major underlying mechanism.

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Killian, Martin, and Thijs E. van Mens. "Risk of Thrombosis, Pregnancy Morbidity or Death in Antiphospholipid Syndrome." Frontiers in Cardiovascular Medicine 9 (March 1, 2022). http://dx.doi.org/10.3389/fcvm.2022.852777.

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The antiphospholipid syndrome is an autoimmune disease characterized by thrombosis and pregnancy morbidity. The manifestations are caused by antibodies targeting cell membrane phospholipids and/or associated proteins. The triggers leading to these antibodies' production are unknown but recent work suggests cross-reactivity between the autoantigens and peptides produced by the intestinal microbiome. Work on how the autoantibodies could cause clinical manifestations implicates different mechanisms. Binding to surface proteins of different cell types can induce intracellular signaling leading to cell activation and tissue factor expression. Complement activation and neutrophil extracellular-traps are also involved, and recent evidence implicates endothelial protein C receptor-lysobisphosphatidic acid complex. Pregnancy is a high-risk situation for antiphospholipid syndrome patients due to the increased risk of thrombosis and obstetric complications. Epidemiological and clinical research on APS is hampered by heterogeneity in populations, testing and treatment strategies. About one in 10 to one in fifty APS pregnancies is complicated by thrombosis, despite treatment. Pregnant patients with prior thrombosis are prescribed therapeutic dose heparins and low dose aspirin. Without prior thrombosis a prophylactic dose is used. The most frequent obstetrical manifestation is recurrent early pregnancy loss. The association of APS antibodies with late pregnancy loss is stronger, however. Prevention of recurrence is achieved with aspirin and prophylactic dose heparin, although the evidence is of low certainty. The third obstetrical classifying manifestation comprises preterm delivery due to placenta-mediated complications and is treated in subsequent pregnancies with aspirin with or without prophylactic dose heparin, again based on low quality evidence. New therapies are under investigation.

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Yao, Zhenlan, Yunsheng Qiao, Xiaofang Li, Jieliang Chen, Jiahui Ding, Lu Bai, Fang Shen, et al. "Exosomes Exploit the Virus Entry Machinery and Pathway To Transmit Alpha Interferon-Induced Antiviral Activity." Journal of Virology 92, no. 24 (October 3, 2018). http://dx.doi.org/10.1128/jvi.01578-18.

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ABSTRACT Alpha interferon (IFN-α) induces the transfer of resistance to hepatitis B virus (HBV) from liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes. However, little is known about the entry machinery and pathway involved in the transmission of IFN-α-induced antiviral activity. In this study, we found that macrophage exosomes uniquely depend on T cell immunoglobulin and mucin receptor 1 (TIM-1), a hepatitis A virus (HAV) receptor, to enter hepatocytes for delivering IFN-α-induced anti-HBV activity. Moreover, two primary endocytic routes for virus infection, clathrin-mediated endocytosis (CME) and macropinocytosis, collaborate to permit exosome entry and anti-HBV activity transfer. Subsequently, lysobisphosphatidic acid (LBPA), an anionic lipid closely related to endosome penetration of virus, facilitates membrane fusion of exosomes in late endosomes/multivesicular bodies (LEs/MVBs) and the accompanying exosomal cargo uncoating. Together, our findings provide comprehensive insights into the transmission route of macrophage exosomes to efficiently deliver IFN-α-induced antiviral substances and highlight the similarities between the entry mechanisms of exosomes and virus.IMPORTANCE Our previous study showed that LNPC-derived exosomes could transmit IFN-α-induced antiviral activity to HBV replicating hepatocytes, but the concrete transmission mechanisms, which include exosome entry and exosomal cargo release, remain unclear. In this study, we found that virus entry machinery and pathway were also applied to exosome-mediated cell-to-cell antiviral activity transfer. Macrophage-derived exosomes distinctively exploit hepatitis A virus receptor for access to hepatocytes. Later, CME and macropinocytosis are utilized by exosomes, followed by exosome-endosome fusion for efficient transfer of IFN-α-induced anti-HBV activity. We believe that understanding the cellular entry pathway of exosomes will be beneficial to designing exosomes as efficient vehicles for antiviral therapy.

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Bañuelos, Cecilia, Abigail Betanzos, Rosario Javier-Reyna, Ausencio Galindo, and Esther Orozco. "Molecular interplays of the Entamoeba histolytica endosomal sorting complexes required for transport during phagocytosis." Frontiers in Cellular and Infection Microbiology 12 (October 27, 2022). http://dx.doi.org/10.3389/fcimb.2022.855797.

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Entamoeba histolytica, the causative agent of human amoebiasis, exhibits a continuous membrane remodelling to exert its virulence properties. During this dynamic process, the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is a key player, particularly in phagocytosis, a virulence hallmark of this parasite. In addition to ESCRT, other molecules contribute to membrane remodelling, including the EhADH adhesin, EhRabs, actin, and the lysobisphosphatidic acid (LBPA). The endocytosis of a prey or molecules induces membrane invaginations, resulting in endosome and multivesicular bodies (MVBs) formation for cargo delivery into lysosomes. Alternatively, some proteins are recycled or secreted. Most of these pathways have been broadly characterized in other biological systems, but poorly described in protozoan parasites. Here, we encompass 10 years of ESCRT research in E. histolytica, highlighting the role of the ESCRT-I and ESCRT-III components and the EhADH and EhVps4-ATPase accessory proteins during phagocytosis. In particular, EhADH exhibits a multifunctional role along the endocytic pathway, from cargo recognition to endosome maturation and lysosomal degradation. Interestingly, the interaction of EhADH with EhVps32 seems to shape a concurrent route to the conventional one for MVBs biogenesis, that could optimize their formation. Furthermore, this adhesin is secreted, but its role in this event remains under study. Other components from the endosomal pathway, such as EhVps23 and LBPA, are also secreted. A proteomic approach performed here, using an anti-LBPA antibody, revealed that some proteins related to membrane trafficking, cellular transport, cytoskeleton dynamics, and transcriptional and translational functions are secreted and associated to LBPA. Altogether, the accumulated knowledge around the ESCRT machinery in E. histolytica, points it out as a dynamic platform facilitating the interaction of molecules participating in different cellular events. Seen as an integrated system, ESCRTs lead to a better understanding of E. histolytica phagocytosis.

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Fu, Min, Xiaowei Zhang, Yiheng Liang, Shouren Lin, Weiping Qian, and Shangrong Fan. "Alterations in Vaginal Microbiota and Associated Metabolome in Women with Recurrent Implantation Failure." mBio 11, no. 3 (June 2, 2020). http://dx.doi.org/10.1128/mbio.03242-19.

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ABSTRACT Recurrent implantation failure (RIF) refers to repeated failure to become pregnant after transferring embryos with normal morphology. However, the pathogenesis of RIF remains unrevealed, especially for those without any pathological features. In this study, we characterized the vaginal microbiota and metabolomes of patients with unexplained RIF, while patients who achieved clinical pregnancy in the first frozen embryo transfer (FET) cycle were used as controls. Based on 16S rRNA gene sequencing of the vaginal microbiota, the vaginal Lactobacillus showed a significant positive correlation with the pregnancy rate, and the RIF group presented higher microbial α-diversity than the control group (P value = 0.016). The metabolomic profile identified 2,507 metabolites, of which 37 were significantly different between the two groups (P value < 0.05, variable importance for the projection [VIP] > 1). Among them, 2′,3-cyclic UMP and inositol phosphate were the top two metabolites that were higher in the RIF group, while glycerophospholipids and benzopyran were important metabolites that were lower in the RIF group. A lack of lysobisphosphatidic acid and prostaglandin metabolized from glycerophospholipids will lead to deferred implantation and embryo crowding. Benzopyran, as a selective estrogen receptor modulator, may affect the outcome of pregnancy. All of the changes in metabolite profiles may result in or from the differential microbiota compositions in RIF patients. In conclusion, significant differences were presented in the vaginal microbiota and metabolomes between patients with unexplained RIF and women who became pregnant in the first FET cycle. For the first time, this study elaborates the possible pathogenesis of RIF by investigating the vaginal microbiota and metabolites in RIF patients. IMPORTANCE In vitro fertilization-embryo transfer (IVF-ET) is now widely applied for treating infertility, and unexplained recurrent implantation failure (RIF) has become a substantial challenge. We hypothesize that vaginal microbial dysbiosis is associated with RIF, as it is linked to many female reproductive diseases. In this study, we characterized the vaginal microbiota and metabolomes of patients with unexplained RIF, while patients who achieved clinical pregnancy in the first IVF cycle were set as controls. In general, significant differences were discovered in the vaginal microbiota and metabolomes between the two groups. This study is the first detailed elaboration of the vaginal microbiota and metabolites associated with RIF. We believe that our findings will inspire researchers to consider the dynamics of microbiomes related to the microenvironment as a critical feature for future studies of nosogenesis not only for RIF but also for other reproductive diseases.

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Journal articles on the topic 'Lysobisphosphatidic Acid'

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