{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:01:22Z","timestamp":1791896482261,"version":"4.3.4"},"reference-count":75,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG)","award":["RTG 2581\u2014417857878"],"award-info":[{"award-number":["RTG 2581\u2014417857878"]}]},{"name":"German Research Foundation (DFG)","award":["INST 93\/1003-1 FUGG"],"award-info":[{"award-number":["INST 93\/1003-1 FUGG"]}]},{"name":"Research Training Group","award":["RTG 2581\u2014417857878"],"award-info":[{"award-number":["RTG 2581\u2014417857878"]}]},{"name":"Research Training Group","award":["INST 93\/1003-1 FUGG"],"award-info":[{"award-number":["INST 93\/1003-1 FUGG"]}]},{"name":"DFG\u2014426173797","award":["RTG 2581\u2014417857878"],"award-info":[{"award-number":["RTG 2581\u2014417857878"]}]},{"name":"DFG\u2014426173797","award":["INST 93\/1003-1 FUGG"],"award-info":[{"award-number":["INST 93\/1003-1 FUGG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The accumulation of lipid droplets (LDs) and ceramides (Cer) is linked to non-alcoholic fatty liver disease (NAFLD), regularly co-existing with type 2 diabetes and decreased immune function. Chronic inflammation and increased disease severity in viral infections are the hallmarks of the obesity-related immunopathology. The upregulation of neutral sphingomyelinase-2 (NSM2) has shown to be associated with the pathology of obesity in tissues. Nevertheless, the role of sphingolipids and specifically of NSM2 in the regulation of immune cell response to a fatty acid (FA) rich environment is poorly studied. Here, we identified the presence of the LD marker protein perilipin 3 (PLIN3) in the intracellular nano-environment of NSM2 using the ascorbate peroxidase APEX2-catalyzed proximity-dependent biotin labeling method. In line with this, super-resolution structured illumination microscopy (SIM) shows NSM2 and PLIN3 co-localization in LD organelles in the presence of increased extracellular concentrations of oleic acid (OA). Furthermore, the association of enzymatically active NSM2 with isolated LDs correlates with increased Cer levels in these lipid storage organelles. NSM2 enzymatic activity is not required for NSM2 association with LDs, but negatively affects the LD numbers and cellular accumulation of long-chain unsaturated triacylglycerol (TAG) species. Concurrently, NSM2 expression promotes mitochondrial respiration and fatty acid oxidation (FAO) in response to increased OA levels, thereby shifting cells to a high energetic state. Importantly, endogenous NSM2 activity is crucial for primary human CD4+ T cell survival and proliferation in a FA rich environment. To conclude, our study shows a novel NSM2 intracellular localization to LDs and the role of enzymatically active NSM2 in metabolic response to enhanced FA concentrations in T cells.<\/jats:p>","DOI":"10.3390\/ijms25063247","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T13:08:43Z","timestamp":1710335323000},"page":"3247","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Rebekka","family":"Schempp","sequence":"first","affiliation":[{"name":"Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Eilts","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biophysics, Biocenter, University of Wuerzburg, 97074 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Sch\u00f6l","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9570-489X","authenticated-orcid":false,"given":"Maria Fernanda","family":"Grijalva Y\u00e9pez","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Fekete","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biology, Julius-von-Sachs-Institute, Biocenter, University of Wuerzburg, 97082 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Wigger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universitaet Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-3275","authenticated-orcid":false,"given":"Fabian","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universitaet Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1888-9595","authenticated-orcid":false,"given":"Burkhard","family":"Kleuser","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universitaet Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6819-4284","authenticated-orcid":false,"given":"Marco","family":"van Ham","sequence":"additional","affiliation":[{"name":"Cellular Proteome Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar","family":"J\u00e4nsch","sequence":"additional","affiliation":[{"name":"Cellular Proteome Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-3219","authenticated-orcid":false,"given":"Markus","family":"Sauer","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biophysics, Biocenter, University of Wuerzburg, 97074 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elita","family":"Avota","sequence":"additional","affiliation":[{"name":"Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1002915","DOI":"10.3389\/fphar.2022.1002915","article-title":"How sphingolipids affect T cells in the resolution of inflammation","volume":"13","author":"Hartel","year":"2022","journal-title":"Front. 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