TY - JOUR A1 - Avota, Elita A1 - Schneider-Schaulies, Sibylle T1 - The Role of Sphingomyelin Breakdown in Measles Virus Immunmodulation JF - Cellular Physiology and Biochemistry N2 - Measles virus (MV) efficiently causes generalized immunosuppression which accounts to a major extent for cases of measles-asscociated severe morbidity and mortality. MV infections alter many functions of antigen presenting cells (APC) (dendritic cells (DCs)) and lymphocytes, yet many molecular targets of the virus remain poorly defined. Cellular interactions and effector functions of DCs and lymphocytes are regulated by surface receptors. Associating with other proteins involved in cell signaling, receptors form part of receptosomes that respond to and transmit external signals through dynamic interctions with the cytoskeleton. Alterations in the composition and metabolism of membrane sphingolipids have a substantial impact on both processes. In this review we focus on the regulation of sphingomyelinase activity and ceramide release in cells exposed to MV and discuss the immunosuppressive role of sphingomyelin breakdown induced by MV. KW - sphingomyelinase KW - measles virus KW - immunosuppression KW - T cell silencing KW - dendritic cell Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120004 SN - 1015-8987 VL - 34 IS - 1 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Schnorr, J.-J. A1 - Dunster, L. M. A1 - Schneider-Schaulies, Jürgen A1 - ter Meulen, Volker T1 - The role of host factors in measles virus persistence N2 - As critical steps in the life cycle oJ measles virus (Mfl), the e.fficiency of uptake into and replication in susceptible host cells are governed by cellular determinants. Measles virus infections of cells of the human CNS are characterized by particular constraints imposed on v1:ral transcription and translation attenuating viral gene Junctions and thus contributing to the pathogenesis oJ MV persistence in these cells. KW - Immunologie KW - CNS infection KW - MV receptor KW - MV transcription KW - unwindase Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-54944 ER - TY - JOUR A1 - Collenburg, Lena A1 - Beyersdorf, Niklas A1 - Wiese, Teresa A1 - Arenz, Christoph A1 - Saied, Essa M. A1 - Becker-Flegler, Katrin Anne A1 - Schneider-Schaulies, Sibylle A1 - Avota, Elita T1 - The activity of the neutral sphingomyelinase is important in T cell recruitment and directional migration JF - Frontiers in Immunology N2 - Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton. KW - LFA-1 KW - neutral sphingomyelinase KW - T cell migration KW - ceramide KW - polarization KW - adhesion Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158944 VL - 8 IS - 1007 ER - TY - JOUR A1 - Geiger, Nina A1 - Kersting, Louise A1 - Schlegel, Jan A1 - Stelz, Linda A1 - Fähr, Sofie A1 - Diesendorf, Viktoria A1 - Roll, Valeria A1 - Sostmann, Marie A1 - König, Eva-Maria A1 - Reinhard, Sebastian A1 - Brenner, Daniela A1 - Schneider-Schaulies, Sibylle A1 - Sauer, Markus A1 - Seibel, Jürgen A1 - Bodem, Jochen T1 - The acid ceramidase is a SARS-CoV-2 host factor JF - Cells N2 - SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor. KW - SARS-CoV-2 KW - ceramides KW - ceramidase KW - fluoxetine KW - acid sphingomyelinase Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286105 SN - 2073-4409 VL - 11 IS - 16 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Schneider-Schaulies, Jürgen A1 - Bayer, M. A1 - Löffler, S. A1 - ter Meulen, V. T1 - Spontaneous and differentiation dependent regulation of measles virus gene expression in human glial cells N2 - The expression of measles virus (MV) in six different permanent human glioma cell lines (D-54, U-251, U-138, U-105, U-373, and D-32) was analyzed. Although all celllines were permissive for productive replication of all MV strains tested, U-251, D-54, and D-32 cells spontaneously revealed restrictions of MV transcription similar to those observed for primary rat astroglial cells and brain tissue. In vitro differentiation of D-54 and U-251 cells by substances affecting tbe intracellular cyclic AMP Ievel caused a significant reduction of tbe expression of tbe viral proteins after 18, 72, and 144 b of infection. This pronounced restriction was not paralleled to a comparable Ievel by an inhibition of tbe syntbesis and biological activity in vitro of virus·specific mRNAs as sbown by quantitative Northem (RNA) blot analyses and in vitro translation. The block in viral protein syntbesis could not be attributed to tbe induction of type I interferon by any of tbe substances tested. Our findings indicate tbat down-regulation of MV gene expression in human brain cells can occur by a cell type-rlependent regulation of tbe viral mRNA transcription and a differentiation-dependent regulation of translation, botb of wbicb may be crucial for the establisbment of persistent MV infections in tbe centrat nervous system. KW - Immunologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-54913 ER - TY - JOUR A1 - Avota, Elita A1 - de Lira, Maria Nathalia A1 - Schneider-Schaulies, Sibylle T1 - Sphingomyelin breakdown in T cells: role of membrane compartmentalization in T cell signaling and interference by a pathogen JF - Frontiers in Cell and Developmental Biology N2 - Sphingolipids are major components of cellular membranes, and at steady-state level, their metabolic fluxes are tightly controlled. On challenge by external signals, they undergo rapid turnover, which substantially affects the biophysical properties of membrane lipid and protein compartments and, consequently, signaling and morphodynamics. In T cells, external cues translate into formation of membrane microdomains where proximal signaling platforms essential for metabolic reprograming and cytoskeletal reorganization are organized. This review will focus on sphingomyelinases, which mediate sphingomyelin breakdown and ensuing ceramide release that have been implicated in T-cell viability and function. Acting at the sphingomyelin pool at the extrafacial or cytosolic leaflet of cellular membranes, acid and neutral sphingomyelinases organize ceramide-enriched membrane microdomains that regulate T-cell homeostatic activity and, upon stimulation, compartmentalize receptors, membrane proximal signaling complexes, and cytoskeletal dynamics as essential for initiating T-cell motility and interaction with endothelia and antigen-presenting cells. Prominent examples to be discussed in this review include death receptor family members, integrins, CD3, and CD28 and their associated signalosomes. Progress made with regard to experimental tools has greatly aided our understanding of the role of bioactive sphingolipids in T-cell biology at a molecular level and of targets explored by a model pathogen (measles virus) to specifically interfere with their physiological activity. KW - T cell KW - sphingomyelinase KW - activation KW - motility KW - measles virus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199168 SN - 2296-634X VL - 7 IS - 152 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Schumacher, Fabian A1 - Wigger, Dominik A1 - Schöl, Marie A1 - Waghmare, Trushnal A1 - Schlegel, Jan A1 - Seibel, Jürgen A1 - Kleuser, Burkhard T1 - Sphingolipids: effectors and Achilles heals in viral infections? JF - Cells N2 - As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention. KW - glycosphingolipids KW - ceramides KW - sphingosine 1-phosphate KW - sphingomyelinase KW - HIV KW - SARS-CoV-2 KW - measles Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245151 SN - 2073-4409 VL - 10 IS - 9 ER - TY - JOUR A1 - Segev, Y. A1 - Rager-Zisman, B. A1 - Isakov, N. A1 - Schneider-Schaulies, Sibylle A1 - ter Meulen, V. A1 - Udem, S. A. A1 - Segal, S. A1 - Wolfson, M. T1 - Reversal of measles virus mediated increase of phosphorylating activity in persistently infected mouse neuroblastoma cells by anti measles antibodies N2 - No abstract available KW - Virologie Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62362 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Liebert, U. G. A1 - Baczko, K. A1 - Cattaneo, R. A1 - Billeter, M. A1 - ter Meulen, V. T1 - Restriction of measles virus gene expression in acute and subacute encephalitis in Lewis rats N2 - No abstract available KW - Virologie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62266 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Liebert, U. G. A1 - Baczko, K. A1 - ter Meulen, V. T1 - Restricted expression of measles virus in primary rat astroglial cells N2 - No abstract available KW - Virologie Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62283 ER -