The Role of Glycosphingolipids in Immune Cell Functions

Zhang, Tao; Waard, Antonius A. de; Wuhrer, Manfred; Spaapen, Robbert M.

doi:10.3389/fimmu.2019.00090

Cited by 111 publications

(115 citation statements)

References 267 publications

(284 reference statements)

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“…Differences in the lipid membrane composition of immune cells have also been observed with respect to the sialic acid containing gangliosides [summarized in (69)]. For example, GM3 is the sole ganglioside found in the membrane of hematopoietic stem cells (70), dendritic cells [summarized in (71)], macrophages (72,73), and monocytes (72,74).…”

Section: Lipid Composition Of Immune Cellsmentioning

confidence: 99%

Impact of Plasma Membrane Domains on IgG Fc Receptor Function

et al. 2020

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Lipid cell membranes not only represent the physical boundaries of cells. They also actively participate in many cellular processes. This contribution is facilitated by highly complex mixtures of different lipids and incorporation of various membrane proteins. One group of membrane-associated receptors are Fc receptors (FcRs). These cell-surface receptors are crucial for the activity of most immune cells as they bind immunoglobulins such as immunoglobulin G (IgG). Based on distinct mechanisms of IgG binding, two classes of Fc receptors are now recognized: the canonical type I FcγRs and select C-type lectin receptors newly referred to as type II FcRs. Upon IgG immune complex induced cross-linking, these receptors are known to induce a multitude of cellular effector responses in a cell-type dependent manner, including internalization, antigen processing, and presentation as well as production of cytokines. The response is also determined by specific intracellular signaling domains, allowing FcRs to either positively or negatively modulate immune cell activity. Expression of cell-type specific combinations and numbers of receptors therefore ultimately sets a threshold for induction of effector responses. Mechanistically, receptor cross-linking and localization to lipid rafts, i.e., organized membrane microdomains enriched in intracellular signaling proteins, were proposed as major determinants of initial FcR activation. Given that immune cell membranes might also vary in their lipid compositions, it is reasonable to speculate, that the cell membrane and especially lipid rafts serve as an additional regulator of FcR activity. In this article, we aim to summarize the current knowledge on the interplay of lipid rafts and IgG binding FcRs with a focus on the plasma membrane composition and receptor localization in immune cells, the proposed mechanisms underlying this localization and consequences for FcR function with respect to their immunoregulatory capacity.

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Section: Lipid Composition Of Immune Cellsmentioning

confidence: 99%

Impact of Plasma Membrane Domains on IgG Fc Receptor Function

et al. 2020

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“…GSLs are involved in lateral and vertical segregation of receptors required for attachment, membrane fusion and endocytosis, as well as in intracellular replication, assembly and release of viruses. In addition, GSLs and their metabolites are inseparably interwoven in signal transduction processes, and the regulation of innate and intrinsic responses of infected target cells (7). Viral-induced elevation of SL levels was shown to be associated with a number of viruses; elevation of GM2-ganglioside and Lactosylceramide was shown upon infection with Zika virus and Hepatitis C virus (HCV), respectively (8,9).…”

Section: Introductionmentioning

confidence: 99%

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Vitner

Avraham

Achdout

et al. 2020

Preprint

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One Sentence Summary: An analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2. AbstractThe need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic.Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target.We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.

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“…The results for KEGG Pathways, were colour coded for each boxplot based on their association with the terms we found most relevant (brain, cancer, heart, immune system, muscle, neurodegenerative disease, skin and other). For cases where there was no direct association, a literature search was done for relevant articles that might show that genes in those pathways were related to brain [28–47], cancer [48], immune system [49–53] and skin [54–58].…”

Section: Resultsmentioning

confidence: 99%

Gene size matters: What determines gene length in the human genome?

Lopes

Altab

Raina

et al. 2020

Preprint

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While it is expected for gene length to be influenced by factors such as intron number and evolutionary conservation, we have yet to fully understand the connection between gene length and function in the human genome.In this study, we show that, as expected, there is a strong positive correlation between gene length and the number of SNPs, introns and protein size. Amongst tissue specific genes, we find that the longest genes are expressed in blood vessels, nerve, thyroid, cervix uteri and brain, while the smallest genes are expressed within the pancreas, skin, stomach, vagina and testis. We report, as shown previously, that natural selection suppresses changes for genes with longer lengths and promotes changes for smaller genes. We also observed that longer genes have a significantly higher number of co-expressed genes and protein-protein interactions. In the functional analysis, we show that bigger genes are often associated with neuronal development, while smaller genes tend to play roles in skin development and in the immune system. Furthermore, pathways related to cancer, neurons and heart diseases tend to have longer genes, with smaller genes being present in pathways related to immune response and neurodegenerative diseases.We hypothesise that longer genes tend to be associated with functions that are important early in life, while smaller genes play a role in functions that are important throughout the organisms’ whole life, like the immune system which require fast responses.Author SummaryEven though the human genome has been fully sequenced, we still do not fully grasp all of its nuances. One such nuance is the length of the genes themselves. Why are certain genes longer than others? Is there a common function shared by longer/smaller genes? What exactly makes gene longer? We tried answering these questions using a variety of analysis. We found that, while there was not a particular strong factor in genes that influenced their size, there could be an influence of several gene characteristics in determining the length of a gene. We also found that longer genes are linked with the development of neurons, cancer, heart diseases and muscle cells, while smaller genes seem to be mostly related with the immune system and the development of the skin. This led us to believe that, whether the gene has an important function early in our life, or throughout our whole lives, or even if the function requires a rapid response, that its gene size will be influenced accordingly.

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The Role of Glycosphingolipids in Immune Cell Functions

Cited by 111 publications

References 267 publications

Impact of Plasma Membrane Domains on IgG Fc Receptor Function

Impact of Plasma Membrane Domains on IgG Fc Receptor Function

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Gene size matters: What determines gene length in the human genome?

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