Abstract
Extracellular vesicles (EVs) are membrane vesicles released by both eukaryotic and prokaryotic cells; they not only serve physiological functions, such as disposal of cellular components, but also play pathophysiologic roles in inflammatory and degenerative diseases. Common molecular mechanisms for EV biogenesis are evident in different cell biological contexts across eukaryotic phyla, and inhibition of this biogenesis may provide an avenue for therapeutic research. The involvement of sphingolipids (SLs) and their enzymes on EV biogenesis and release has not received much attention in current research. Here, we review how SLs participate in EV biogenesis by shaping membrane curvature and how they contribute to EV action in target cells. First, we describe how acid and neutral SMases, by generating the constitutive SL, ceramide, facilitate biogenesis of EVs at the plasma membrane and inside the endocytic compartment. We then discuss the involvement of other SLs, such as sphingosine-1-phosphate and galactosyl-sphingosine, in EV formation and cargo sorting. Last, we look ahead at some biological effects of EVs mediated by changes in SL levels in recipient cells.
Highlights
Extracellular vesicles (EVs) are membrane vesicles released by both eukaryotic and prokaryotic cells; they serve physiological functions, such as disposal of cellular components, and play pathophysiologic roles in inflammatory and degenerative diseases
This study showed that SM is more represented in exosomes secreted across apical compared with the basolateral plasma membrane [107]. iii) SL profiling of human oligodendroglioma (HOG) cell-derived exosomes, revealing differences in the SL composition, in particular of C16, C24, and C24:1-Cer species; C16, C24, and C24:1-dihydroCer species; and C16, C24, and C24:1-SM species, between exosomes released constitutively or under stimulation with inflammatory cytokines [108]. iv) The work by Carayon et al [109] showing that the exosomal content of Cer versus SM is significantly increased during reticulocyte maturation. v) The study by Baig et al [110] demonstrating that GM3 levels are significantly downregulated in MVs derived from syncytiotrophoblasts of preeclampsia patients
The authors of this study showed that Cer levels are regulated by Neutral SMase (n-SMase) 2 in astrocytes and are critical for astrocyte apoptosis caused by A, which is not observed in n-SMase 2-deficient cells
Summary
Plasma and endosomal membranes display an asymmetric lipid distribution, with SM and phosphatidylcholine (PC) enriched on the noncytosolic (luminal) side, and PS and other lipid classes enriched in the leaflet facing cytosol [36]. Truman et al [84] found that a-SMase is activated in response to engagement of surface Fc receptors by oxidized LDL-containing immune complexes and plays a role in the release of IL-1 in association with exosomes in the human macrophage cell line, U937 This evidence was documented by reduced exosome and IL-1 secretion from cells in which a-SMase was pharmacologically (desipramine) or genetically inhibited (a-SMase siRNA) [84]. P38 MAPK, which is essential for P2X7dependent a-SMase translocation onto the plasma membrane, is activated downstream of TRPV1 receptors [88] and its inhibition blocks capsaicin-induced MV shedding from microglia in vitro and in cortical brain slices [85], consistent with a role of a-SMase in TRPV1-dependent MV production. While clearing some of the accumulated SL material via EV secretion, brain cells may shuttle pathogenic SLs [e.g., psychosine or proapoptotic Cer [56]] to cells that are not intrinsically affected, contributing to establishing non-cell-autonomous defects [100]
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