Search

The maintenance of a diverse and non-homogeneous lipid composition in cell membranes is crucial for a multitude of cellular processes. One important example is transbilayer lipid asymmetry, which refers to a difference in lipid composition between the two leaflets of a cellular membrane. Transbilayer asymmetry is especially pronounced at the plasma membrane, where at resting state, negatively-charged phospholipids such as phosphatidylserine (PS) are almost exclusively restricted to the cytosolic leaflet, whereas sphingolipids are mostly found in the exoplasmic leaflet. Transbilayer movement of lipids is inherently slow, and for a fast cellular response, for example during apoptosis, transmembrane proteins termed scramblases facilitate the movement of polar/charged lipid headgroups through the membrane interior. In recent years, an expanding number of proteins from diverse families have been suggested to possess a lipid scramblase activity. Members of TMEM16 and XKR proteins have been implicated in blood clotting and apoptosis, whereas the scrambling activity of ATG9 and TMEM41B/VMP1 proteins contributes to the synthesis of autophagosomal membrane during autophagy. Structural studies, in vitro reconstitution of lipid scrambling, and molecular dynamics simulations have significantly advanced our understanding of the molecular mechanisms of lipid scrambling and helped delineate potential lipid transport pathways through the membrane. A number of examples also suggest that lipid scrambling activity can be combined with another activity, as is the case for TMEM16 proteins, which also function as ion channels, rhodopsin in the photoreceptor membrane, and possibly other G-protein coupled receptors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans-Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. We previously identified mutations in sphingomyelin synthase SMS2 that cause osteoporosis and skeletal dysplasia. Here, we show that SMS2 variants linked to the most severe bone phenotypes retain full enzymatic activity but fail to leave the ER owing to a defective autonomous ER export signal. Cells harboring pathogenic SMS2 variants accumulate sphingomyelin in the ER and display a disrupted transbilayer sphingomyelin asymmetry. These aberrant sphingomyelin distributions also occur in patient-derived fibroblasts and are accompanied by imbalances in cholesterol organization, glycerophospholipid profiles, and lipid order in the secretory pathway. We postulate that pathogenic SMS2 variants undermine the capacity of osteogenic cells to uphold nonrandom lipid distributions that are critical for their bone forming activity.

Many biological membranes present an asymmetric lipid distribution between the two leaflets that is known as the transbilayer lipid asymmetry. This asymmetry is essential for cell survival and its loss is related to apoptosis. In mammalian and yeast cells, ATP-dependent transport of lipids to the cytosolic side of the biological membranes, carried out by so-called lipid flippases, contributes to the transbilayer lipid asymmetry. Most of these lipid flippases belong to the P4-ATPase protein family, which is also present in plants. In this review, we summarize the relatively scarce literature concerning the presence of transbilayer lipid asymmetry in different plant cell membranes and revise the potential role of lipid flippases of the P4-ATPase family in generation and/or maintenance of this asymmetry., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology.)

Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans- Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. We previously identified mutations in sphingomyelin synthase SMS2 that cause osteoporosis and skeletal dysplasia. Here, we show that SMS2 variants linked to the most severe bone phenotypes retain full enzymatic activity but fail to leave the ER owing to a defective autonomous ER export signal. Cells harboring pathogenic SMS2 variants accumulate sphingomyelin in the ER and display a disrupted transbilayer sphingomyelin asymmetry. These aberrant sphingomyelin distributions also occur in patient-derived fibroblasts and are accompanied by imbalances in cholesterol organization, glycerophospholipid profiles, and lipid order in the secretory pathway. We postulate that pathogenic SMS2 variants undermine the capacity of osteogenic cells to uphold nonrandom lipid distributions that are critical for their bone forming activity., Competing Interests: TS, JP, MF, DD, MB, BS, AH, MP, LB, PT, OM, JP, YK, CB, AK, KM, JH No competing interests declared, (© 2022, Sokoya, Parolek et al.)

Abstract: Background: Nitric oxide (NO) plays a vital role in maintaining the survivability of circulating erythrocytes. Here we have investigated whether NO depletion associated with visceral leishmaniasis (VL) is responsible for the reduced survival of erythrocytes observed during the disease. Methods: Infected hamsters were treated with standard anti-leishmanial sodium stibogluconate (SAG) and NO donor isosorbide dinitrate (ISD). Erythrophagocytosis by macrophages was determined by labelling the cells with FITC followed by flow cytometry. Aggregation of band3 was estimated from band3 associated EMA fluorescence. Caspase 3 activity was measured using immunosorbent assay kit. Phosphatidylserine (PS) externalization and cell shrinkage were determined using annexin V. Aminophspholipid translocase and scramblase activities were measured following NBD-PS and NBD-PC internalization, respectively. Results: Impairment of both synthesis and uptake of NO resulted in decreased bioavailability of this signaling molecule in erythrocytes in VL. NO level was replenished after simultaneous treatment with ISD and SAG. Combination treatment decreased red cell apoptosis in infected animals by deactivating caspase 3 through s-nitrosylation. Drug treatment prevented infection-mediated ATP depletion and altered calcium homeostasis in erythrocytes. Improved metabolic environment effectively amended dysregulation of aminophospholipid translocase and scramblase, which in turn reduced cell shrinkage, and exposure of phosphatidylserine on the cell surface under the diseased condition. Conclusion and general significance: In this study, we have identified NO depletion to be an important factor in promoting premature hemolysis with the progress of leishmanial infection. The study implicates NO to be a possible target for future drug development towards the promotion of erythrocyte survival in VL. [ABSTRACT FROM AUTHOR]