Ceramide and other sphingolipids in cellular responses

Formerly considered to serve only as structural components, sphingolipids are emerging as an important group of signaling molecules involved in many cellular events, including cell growth, senescence, meiotic maturation, and cell death. They are also implicated in functions such as inflammation and the responses to heat shock and genotoxic stress. Defects in the metabolism of sphingolipids are related to various genetic disorders, and sphingolipids have the potential to serve as therapeutic agents for human diseases such as colon cancer and viral or bacterial infections. The best-studied member of this family, ceramide, which also serves as the structural back-bone for other sphingolipids, is an important mediator in multiple cellular signaling pathways. The metabolism and functions of sphingolipids are discussed in this review, with a focus on ceramide regulation in various cellular responses.     

Suppressor gene analysis reveals an essential role for sphingolipids in transport of glycosylphosphatidylinositol-anchored proteins in Saccharomyces cerevisiae.

Sphingolipids are normally necessary for growth of Saccharomyces cerevisiae cells, but mutant strains that bypass the need for sphingolipids have been identified. Such bypass mutants fail to grow under stressful conditions, including low pH (pH 4.1), when they lack sphingolipids. To begin to understand why sphingolipids seem to be necessary for coping with low-pH stress, we screened a genomic library and selected a suppressor gene, CWP2 (cell wall protein 2), that when present in multiple copies partially compensates for the lack of sphingolipids and enhances survival at low pH. To explain these results, we present evidence that sphingolipids are required for a normal rate of transport of glycosylphosphatidylinositol (GPI)-anchored proteins, including Cwp2 and Gas1/Gpg1, from the endoplasmic reticulum (ER) to the Golgi apparatus. The effect of sphingolipids is specific for transport of GPI-anchored proteins because no effect on the rate of transport of carboxypeptidase Y, a non-GPI-anchored protein, was observed. Since the Gasl protein accumulated in the ER with a GPI anchor in cells lacking sphingolipids, we conclude that sphingolipids are not necessary for anchor attachment. Therefore, sphingolipids must be necessary for a step in formation of COPII vesicles or for their transport to the Golgi apparatus. Our data identify the Cwp2 protein as a vital component in protecting cells from the stress of low pH.     

鞘脂在植物-真菌互作中的分子调控机制研究进展

鞘脂是细胞生物膜结构的重要组分, 鞘脂及其代谢产物参与许多重要的信号转导过程。在植物-真菌互作中, 植物鞘脂的主要作用是诱导细胞发生程序性死亡; 真菌鞘脂既能引起植物死亡, 也能诱导植物产生抗病性。该文总结了植物和真菌鞘脂的结构及代谢特点, 综述了鞘脂参与调控植物-真菌互作的分子机制研究进展, 并展望了植物-真菌共生关系中鞘脂作用的研究方向。     

鞘脂在植物-真菌互作中的分子调控机制研究进展

鞘脂是细胞生物膜结构的重要组分, 鞘脂及其代谢产物参与许多重要的信号转导过程。在植物-真菌互作中, 植物鞘脂的主要作用是诱导细胞发生程序性死亡; 真菌鞘脂既能引起植物死亡, 也能诱导植物产生抗病性。该文总结了植物和真菌鞘脂的结构及代谢特点, 综述了鞘脂参与调控植物-真菌互作的分子机制研究进展, 并展望了植物-真菌共生关系中鞘脂作用的研究方向。     

Sphingolipid uptake by cultured cells: complex aggregates of cell sphingolipids with serum proteins and lipoproteins are rapidly catabolized

Human fibroblasts, rat neurons, and murine neuroblastoma cells, cultured in the presence of fetal calf serum, were fed with [1-(3)H]sphingosine to radiolabel sphingolipids. The fate of cell sphingolipids, the release of sphingolipids in the culture medium, the interaction of sphingolipids with the proteins and lipoproteins of fetal calf serum, and the fate of sphingolipids taken up by the cells were investigated. For this latter purpose, the culture medium containing radioactive sphingolipids was delivered to nonlabeled cells. The presence of tritium at position 1 of sphingosine allowed us to follow the extent of sphingolipid catabolism by measuring the production of radioactive phosphatidylethanolamine and proteins by recycling the radioactive ethanolamine formed during sphingosine catabolism and the production of tritiated water. We confirmed that in cells the recycling of sphingosine occurred to a high extent and that only a minor portion of cell sphingolipids was catabolized to the small fragments of ethanolamine and water. Cell sphingolipids were released in the culture medium, where they formed large lipoproteic aggregates at a rate of about 12% per day. Released sphingolipids were taken up by the cells and catabolized to the sphingosine and then to ethanolamine, and recycling of sphingosine was not observed. This suggests that in the presence of fetal calf serum in the culture medium, exogenous sphingolipids directly reach the lysosomes, were they are entirely catabolized. Thus, the trafficking of sphingolipids from cells to the extracellular environment and from this to other cells does not allow the modification of the plasma membrane composition.     

Bioeffector Sphingolipids Devoid of 4E-Double Bond in the Sphingoid Hydrocarbon Chain

The bioregulatory functions of sphingolipids devoid of 4-E-double bond in the sphingoid chain are discussed; the sphingolipids are shown to be biologically active.     

植物鞘脂的结构、代谢途径及其功能

众所周知, 鞘脂是生物膜结构的重要组成成分, 随着鞘脂在动物和酵母中的深入研究发现, 鞘脂及其代谢产物是一类很重要的活性分子, 它们参与调节细胞的生长、分化、衰老和细胞程序性死亡等许多重要的信号转导过程。鞘脂在植物中的研究最近几年才开始, 植物鞘脂的功能还不十分清楚。最近的研究发现, 鞘脂及其代谢产物在植物中也起着很重要的信号分子作用。该文详细总结了鞘脂在植物中的结构、代谢途径和主要生物学功能, 并结合实验室的工作对植物鞘脂的功能研究进行了展望。     

Sphingolipids and cell signaling: Involvement in apoptosis and atherogenesis

This review considers various functional aspects of cell sphingolipids (sphingomyelin, ceramides) and lysosphingolipids (sphingosine-1-phosphate (S1P) and sphingosine phosphorylcholine). Good evidence now exists that they are actively involved in numerous cell-signaling processes. The enzymes responsible for formation and interconversion of cell sphingolipids (sphingomyelinases, ceramidase, sphingosine kinase, S1P-lyase) exhibit high sensitivity to various stimulating factors. This determines the content of individual cell sphingolipids and therefore the mode of cell response. Special attention is paid to preferential localization of sphingolipids in the rigid plasma membrane domains (rafts) coupled to many signal proteins. The suggestion is discussed that ceramide signaling may be based on the modification of fine molecular interactions in lipid rafts, resulting in its clusterization inducing the signal transduction. The review also highlights involvement of sphingolipids in cell proliferation, apoptosis, and in processes implicated to atherosclerosis.     

植物鞘脂的结构、代谢途径及其功能

众所周知,鞘脂是生物膜结构的重要组成成分,随着鞘脂在动物和酵母中的深入研究发现,鞘脂及其代谢产物是一类很重要的活性分子,它们参与调节细胞的生长、分化、衰老和细胞程序性死亡等许多重要的信号转导过程。鞘脂在植物中的研究最近几年才开始,植物鞘脂的功能还不十分清楚。最近的研究发现,鞘脂及其代谢产物在植物中也起着很重要的信号分子作用。该文详细总结了鞘脂在植物中的结构、代谢途径和主要生物学功能,并结合实验室的工作对植物鞘脂的功能研究进行了展望。     

Separation and identification of major plant sphingolipid classes from leaves

Sphingolipids are major components of the plasma membrane, tonoplast, and other endomembranes of plant cells. Previous compositional analyses have focused only on individual sphingolipid classes because of the widely differing polarities of plant sphingolipids. Consequently, the total content of sphingolipid classes in plants has yet to be quantified. In addition, the major polar sphingolipid class in the model plant Arabidopsis thaliana has not been previously determined. In this report, we describe the separation and quantification of sphingolipid classes from A. thaliana leaves using hydrolysis of sphingolipids and high performance liquid chromatography (HPLC) analysis of o-phthaldialdehyde derivatives of the released long-chain bases to monitor the separation steps. An extraction solvent that contained substantial proportions of water was used to solubilized >95% of the sphingolipids from leaves. Neutral and charged sphingolipids were then partitioned by anion exchange solid phase extraction. HPLC analysis of the charged lipid fraction from A. thaliana revealed only one major anionic sphingolipid class, which was identified by mass spectrometry as hexose-hexuronic-inositolphosphoceramide. The neutral sphingolipids were predominantly composed of monohexosylceramide with lesser amounts of ceramides. Extraction and separation of sphingolipids from soybean and tomato showed that, like A. thaliana, the neutral sphingolipids consisted of ceramide and monohexosylceramides; however, the major polar sphingolipid was found to be N-acetyl-hexosamine-hexuronic-inositolphosphoceramide. In extracts from A. thaliana leaves, hexosehexuronic-inositolphosphoceramides, monohexosylceramides, and ceramides accounted for approximately 64, 34, and 2% of the total sphingolipids, respectively, suggesting an important role for the anionic sphingolipids in plant membranes.     

The relationship between the biological functions of sphingolipids and their chemical structure

The interrelation between the bioeffector functions of sphingolipids and their chemical structure is reviewed. The effects of modifications of sphingoid functional groups on the bioregulatory properties of sphingolipids in cell proliferation, differentiation, and apoptosis are discussed.     

The interrelation between the biological functions of sphingolipids and their chemical structure

The interrelation between the bioeffector functions of sphingolipids and their chemical structure is reviewed. The effects of modifications of sphingoid functional groups on the bioregulatory properties of sphingolipids in cell proliferation, differentiation, and apoptosis are discussed.     

Sphingolipids and impaired hypoxic stress responses in Huntington disease

Huntington disease (HD) is a debilitating, currently incurable disease. Protein aggregation and metabolic deficits are pathological hallmarks but their link to neurodegeneration and symptoms remains debated.Here, we summarize alterations in the levels of different sphingolipids in an attempt to characterize sphingolipid patterns specific to HD, an additional molecular hallmark of the disease. Based on the crucial role of sphingolipids in maintaining cellular homeostasis, the dynamic regulation of sphingolipids upon insults and their involvement in cellular stress responses, we hypothesize that maladaptations or blunted adaptations, especially following cellular stress due to reduced oxygen supply (hypoxia) contribute to the development of pathology in HD. We review how sphingolipids shape cellular energy metabolism and control proteostasis and suggest how these functions may fail in HD and in combination with additional insults. Finally, we evaluate the potential of improving cellular resilience in HD by conditioning approaches (improving the efficiency of cellular stress responses) and the role of sphingolipids therein.Sphingolipid metabolism is crucial for cellular homeostasis and for adaptations following cellular stress, including hypoxia. Inadequate cellular management of hypoxic stress likely contributes to HD progression, and sphingolipids are potential mediators. Targeting sphingolipids and the hypoxic stress response are novel treatment strategies for HD.     

Sphingolipids in mitochondria

Sphingolipids are bioactive lipids found in cell membranes that exert a critical role in signal transduction. In recent years, it has become apparent that sphingolipids participate in growth, senescence, differentiation and apoptosis. The anabolism and catabolism of sphingolipids occur in discrete subcellular locations and consist of a strictly regulated and interconnected network, with ceramide as the central hub. Altered sphingolipid metabolism is linked to several human diseases. Hence, an advanced knowledge of how and where sphingolipids are metabolized is of paramount importance in order to understand the role of sphingolipids in cellular functions. In this review, we provide an overview of sphingolipid metabolism. We focus on the distinct pathways of ceramide synthesis, highlighting the mitochondrial ceramide generation, transport of ceramide to mitochondria and its role in the regulation of mitochondrial-mediated apoptosis, mitophagy and implications to disease. We will discuss unanswered questions and exciting future directions. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.     

Ceramide metabolism in brain

Summary Ceramide is the fundamental structure and key intermediate of all sphingolipids. Biosynthesis and catabolism of brain ceramide, especially their relationship to the metabolism of more complex sphingolipids in brain, are reviewed. Human genetic diseases which involve altered ceramide metabolism are also discussed.     

病毒介导的海洋球石藻(Coccolithophores)鞘脂类代谢调控

海洋球石藻(Coccolithophores)是一种全球广泛分布且具有重要生态功能的真核浮游植物,有些种类是大洋和近岸常见的赤潮种。自然海域中,病毒感染是导致球石藻死亡和赤潮消亡的一个关键因素。基于一株海洋球石藻Emiliania huxleyi及其特异性裂解病毒全基因组测序注释的结果,研究者们发现病毒可能通过基因横向转移从宿主基因组中获取了一系列与鞘脂类代谢相关的关键酶基因,进而在一定程度上掌控了宿主鞘脂类代谢,大量合成、积累病毒性鞘脂类物质,并最终诱导宿主细胞以凋亡的形式死亡。因此,病毒介导的宿主鞘脂类代谢在调节病毒与宿主间相互作用中具有重要意义。本文着重综述海洋球石藻病毒与宿主间的基因横向转移、病毒介导的宿主鞘脂类代谢特点及其生态学意义,以期深入了解海洋球石藻病毒与宿主间复杂的相互作用关系。     

Very long chain sphingolipids: Tissue expression, function and synthesis

Forecort membranes of all mammalian cells contain, in addition to phosphoglycerolipids and cholesterol, substantial amounts of sphingolipids. In most cells the acyl moieties of these sphingolipids are of long chain type (C16-24) and often saturated. However, epidermal keratinocytes and male germ cells largely express sphingolipids with very long chain-acyl moieties (C26-C36) during their differentiation and maturation. This expression seems to depend on CerS3, one of six ceramide synthases. However, the complex biosynthetic sequence for both epidermal and testicular sphingolipids has not been elucidated completely. Whereas it is established that omega-hydroxylated very long chain-sphingolipids are essential for proper skin barrier function, the role of polyunsaturated very long chain-sphingolipids (ceramides, sphingomyelins and glycosphingolipids) in differentiating spermatocytes/spermatids is just beginning to be revealed.     

Effects of Bacteroides Phosphosphingolipids on Murine Neutrophils

Bacteroides and related species formerly classified in the genus Bacteroides have phosphosphingolipids as their membrane lipid. To evaluate the possible involvement of bacterial sphingolipids in the infection process, the effects of Bacteroides sphingolipids on murine neutrophils were examined in this study. Observation by differential interference contrast microscopy showed morphological changes in murine neutrophils in the presence of the sphingolipids, indicating biological activity by the Bacteroides sphingolipids. The lipids dose-dependently inhibited superoxide release from the neutrophils stimulated with phorbol myristate acetate. This observation suggests that bactericidal activity of the neutrophils may be affected by Bacteroides sphingolipids. Taken together, these findings provide evidence that Bacteroides sphingolipids may contribute to the pathogenesis of mixed infections by direct inhibition of neutrophil function.     

Sphingolipids as modulators of membrane proteins

The diversity of the transmembranome of higher eukaryotes is matched by an enormous diversity of sphingolipid classes and molecular species. The intrinsic properties of sphingolipids are not only suited for orchestrating lateral architectures of biological membranes, but their molecular distinctions also allow for the evolution of protein motifs specifically recognising and interacting with individual lipids. Although various reports suggest a role of sphingolipids in membrane protein function, only a few cases have determined the specificity of these interactions. In this review we discuss examples of specific protein–sphingolipid interactions for which a modulator-like dependency on sphingolipids was assigned to specific proteins. These novel functions of sphingolipids in specific protein–lipid assemblies contribute to the complexity of the sphingolipid classes and other molecular species observed in animal cells. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

The Role of Sphingolipids in Neuronal Development: Lessons from Models of Sphingolipid Storage Diseases

The study of sphingolipids has undergone a renaissance over the past decade due to the realization that these lipids are involved in a variety a biological processes, such as differentiation, apoptosis, cell growth, and cell migration. In the nervous system, sphingolipids, particularly gangliosides, have attracted particular attention as they occur at high levels and their levels change in a developmentally regulated program. Despite the fact that a large body of data has accumulated on the expression and metabolism of individual gangliosides within specific brain regions, the role of individual gangliosides in neuronal development is still poorly understood, and their specific functions are only now beginning to be elucidated. In the present article, we discuss various aspects of our current knowledge concerning the involvement of sphingolipids and gangliosides in neuronal development, and then discuss some recent findings that shed light on the role of sphingolipids and gangliosides obtained with animal models of sphingolipid and other lysosomal storage diseases.