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Cancer cells frequently alter their lipids to grow and adapt to their environment 1 – 3 . Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8 + T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion. Functional genomics and lipidomic analyses reveal that sphingolipid synthesis is required for tumour immune evasion and tumour growth in vivo, mediated in part by the impact of glycosphingolipid synthesis on cell surface expression of IFNγ receptors.

Glycosphingolipids (GSLs) exhibit a variety of functions in cellular differentiation and interaction. Also, they are known to play a role as receptors in pathogen invasion. A less well-explored feature is the role of GSLs in immune cell function which is the subject of this review article. Here we summarize knowledge on GSL expression patterns in different immune cells. We review the changes in GSL expression during immune cell development and differentiation, maturation, and activation. Furthermore, we review how immune cell GSLs impact membrane organization, molecular signaling, and trans-interactions in cellular cross-talk. Another aspect covered is the role of GSLs as targets of antibody-based immunity in cancer. We expect that recent advances in analytical and genome editing technologies will help in the coming years to further our knowledge on the role of GSLs as modulators of immune cell function.

Glycosphingolipids (GSLs) constitute the most structurally diverse subgroup of the sphingolipid family and play crucial roles in a wide variety of cellular functions. The expression of GSLs is tightly controlled during development, with each GSL series exhibiting distinct functional roles in adhesion or signaling, depending on cell type. Genetic defects in lysosomal GSL-degrading enzymes result in GSL storage disorders. However, aberrant and increased expression of GSLs has also been observed in various cancer cells, promoting tumor survival and impairing anti-tumor immunity. Additionally, viruses, pathogens, and bacterial toxins have been found to bind to host GSLs. Therefore, inhibiting GSL synthesis could be a potential therapeutic strategy for such infections or cancers. Here, we discuss the synthesis and classification of GSLs and review their role in disease and treatment.

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4⁺ T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.

Glucosylceramide (GlcCer), a common precursor of different glycosphingolipids, is shown to be channelled to two distinct pathways in the Golgi; non-vesicular transport from the cis - to trans -Golgi network results in the synthesis of the globo series of glycosphingolipids, whereas vesicular transport is the main source of GlcCer for ganglioside synthesis in the Golgi cisternae. Dual carriageway in the Golgi transport complex Newly synthesized lipids are transported across the Golgi network through vesicular and non-vesicular mechanisms. This study demonstrates that glucosylceramide (GlcCer), which is the common precursor of various glycosphingolipids, is channelled to two topologically distinct pathways in the Golgi. Non-vesicular transport of GlcCer from its site of synthesis in the cis -Golgi to the trans -Golgi results in the synthesis of the globo-series (Gb3) of glycosphingolipids, whereas vesicular transport is the major source of GlcCer for the synthesis of gangliosides in the Golgi cisternae. Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)—the common precursor of the different series of glycosphingolipids—that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1 ). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis -Golgi to the trans -Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer—vesicular and non-vesicular—through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans -Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway.

Sphingolipids and glycosphingolipids are emerging as major players in many facets of cell physiology and pathophysiology. We now present an overview of sphingolipid biochemistry and physiology, followed by a brief presentation of recent advances in translational research related to sphingolipids. In discussing sphingolipid biochemistry, we focus on the structure of sphingolipids, and their biosynthetic pathways--the recent identification of most of the enzymes in this pathway has led to significant advances and better characterization of a number of the biosynthetic steps, and the relationship between them. We then discuss some roles of sphingolipids in cell physiology, particularly those of ceramide and sphingosine-1-phosphate, and mention current views about how these lipids act in signal transduction pathways. We end with a discussion of sphingolipids and glycosphingolipids in the etiology and pathology of a number of diseases, such as cancer, immunity, cystic fibrosis, emphysema, diabetes, and sepsis, areas in which sphingolipids are beginning to take a central position, even though many of the details remain to be elucidated.

GBA1 mutations that encode lysosomal β-glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher disease (GD) and are strong risk factors for synucleinopathies, including Parkinson’s disease and Lewy body dementia. Only a subset of subjects with GBA1 mutations exhibit neurodegeneration, and the factors that influence neurological phenotypes are unknown. We find that α-synuclein (α-syn) neuropathology induced by GCase depletion depends on neuronal maturity, the physiological state of α-syn, and specific accumulation of long-chain glycosphingolipid (GSL) GCase substrates. Reduced GCase activity does not initiate α-syn aggregation in neonatal mice or immature human midbrain cultures; however, adult mice or mature midbrain cultures that express physiological α-syn oligomers are aggregation prone. Accumulation of long-chain GSLs (≥C22), but not shortchain species, induced α-syn pathology and neurological dysfunction. Selective reduction of long-chain GSLs ameliorated α-syn pathology through lysosomal cathepsins. We identify specific requirements that dictate synuclein pathology in GD models, providing possible explanations for the phenotypic variability in subjects with GCase deficiency.

Marine viruses that infect phytoplankton are recognized as a major ecological and evolutionary driving force, shaping community structure and nutrient cycling in the marine environment. Little is known about the signal transduction pathways mediating viral infection. We show that viral glycosphingolipids regulate infection of Emiliania huxleyi, a cosmopolitan coccolithophore that plays a major role in the global carbon cycle. These sphingolipids derive from an unprecedented cluster of biosynthetic genes in Coccolithovirus genomes, are synthesized de novo during lytic infection, and are enriched in virion membranes. Purified glycosphingolipids induced biochemical hallmarks of programmed cell death in an uninfected host. These lipids were detected in coccolithophore populations in the North Atlantic, which highlights their potential as biomarkers for viral infection in the oceans.

Cancer‐associated glycosphingolipids have been used as markers for diagnosis and targets for immunotherapy of malignant tumors. Recent progress in the analysis of their implications in the malignant properties of cancer cells revealed that cancer‐associated glycosphingolipids are not only tumor markers, but also functional molecules regulating various signals introduced by membrane microdomains, lipid rafts. In particular, a novel approach, enzyme‐mediated activation of radical sources combined with mass spectrometry, has enabled us to clarify the mechanisms by which cancer‐associated glycosphingolipids regulate cell signals based on the interaction with membrane molecules and formation of molecular complexes on the cell surface. Novel findings obtained from these approaches are now providing us with insights into the development of new anticancer therapies targeting membrane molecular complexes consisting of cancer‐associated glycolipids and their associated membrane molecules. Thus, a new era of cancer‐associated glycosphingolipids has now begun. Cancer‐associated glycosphingolipids have been used as markers for diagnosis and targets for immunotherapy of malignant tumors. Recent studies have revealed that they are not only tumor markers, but also functional molecules regulating various signals at lipid rafts. In particular, a novel approach, enzyme‐mediated activation of radical sources combined with mass spectrometry, has enabled us to clarify the mechanisms by which cancer‐associated glycosphingolipids regulate cell signals, leading to development of novel therapies targeting membrane molecular complexes consisting of cancer‐associated glycolipids and their associating membrane molecules.

Glycosylphosphatidylinositol (GPI)-anchored proteins and glycosphingolipids interact with each other in the mammalian plasma membranes, forming dynamic microdomains. How their interaction starts in the cells has been unclear. Here, based on a genome-wide CRISPR-Cas9 genetic screen for genes required for GPI side-chain modification by galactose in the Golgi apparatus, we report that β1,3-galactosyltransferase 4 (B3GALT4), the previously characterized GM1 ganglioside synthase, additionally functions in transferring galactose to the N -acetylgalactosamine side-chain of GPI. Furthermore, B3GALT4 requires lactosylceramide for the efficient GPI side-chain galactosylation. Thus, our work demonstrates previously unexpected functional relationships between GPI-anchored proteins and glycosphingolipids in the Golgi. Through the same screening, we also show that GPI biosynthesis in the endoplasmic reticulum (ER) is severely suppressed by ER-associated degradation to prevent GPI accumulation when the transfer of synthesized GPI to proteins is defective. Our data demonstrates cross-talks of GPI biosynthesis with glycosphingolipid biosynthesis and the ER quality control system. Glycosylphosphatidylinositol (GPI) anchors are found on many cell surface proteins but their biosynthesis is not fully understood. Here, the authors identify genes involved in GPI galactosylation and reveal functional connections between GPI processing, glycosphingolipid biosynthesis and ER-associated degradation.