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Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways
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SYSNO ASEP 0552089 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways Author(s) Bugajev, Viktor (UMG-J) RID
Paulenda, Tomáš (UMG-J)
Utekal, Pavol (UMG-J)
Mrkáček, Michal (UMG-J)
Hálová, Ivana (UMG-J) RID, ORCID
Kuchař, L. (CZ)
Kuda, Ondřej (FGU-C) RID, ORCID, SAI
Vávrová, Petra (UMG-J)
Schuster, Bjorn (UMG-J)
Fuentes-Liso, Sergio (UMG-J)
Potůčková, Lucie (UMG-J)
Smrž, D. (CZ)
Černohouzová, Sára (UMG-J)
Dráberová, Lubica (UMG-J) RID
Bambousková, Monika (UMG-J)
Dráber, Petr (UMG-J) RIDNumber of authors 16 Article number 100121 Source Title Journal of Lipid Research. - : Elsevier - ISSN 0022-2275
Roč. 62, September (2021)Number of pages 18 s. Publication form Online - E Language eng - English Country US - United States Keywords sphingolipids ; leukotrienes ; immunology ; signal transduction ; inflammation ; peritoneal-derived mast cells ; ER membrane domains ; lipid mass spectrometry ; hplc Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects GA18-18521S GA ČR - Czech Science Foundation (CSF) GA17-20915S GA ČR - Czech Science Foundation (CSF) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018129 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0016045 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 ; FGU-C - RVO:67985823 UT WOS 000709953200005 EID SCOPUS 85118308975 DOI 10.1016/j.jlr.2021.100121 Annotation Leukotrienes (LTs) and sphingolipids are critical lipid mediators participating in numerous cellular signal transduction events and developing various disorders, such as bronchial hyperactivity leading to asthma. Enzymatic reactions initiating production of these lipid mediators involve 5lipoxygenase (5-LO)-mediated conversion of arachidonic acid to LTs and serine palmitoyltransferase (SPT)-mediated de novo synthesis of sphingolipids. Previous studies have shown that endoplasmic reticulum membrane protein ORM1-like protein 3 (ORMDL3) inhibits the activity of SPT and subsequent sphingolipid synthesis. However, the role of ORMDL3 in the synthesis of LTs is not known. In this study, we used peritoneal-derived mast cells isolated from ORMDL3 KO or control mice and examined their calcium mobilization, degranulation, NF-KB inhibitor-alpha phosphorylation, and TNF-alpha production. We found that peritoneal-derived mast cells with ORMDL3 KO exhibited increased responsiveness to antigen. Detailed lipid analysis showed that compared with WT cells, ORMDL3-deficient cells exhibited not only enhanced production of sphingolipids but also of LT signaling mediators LTB4, 6t-LTB4, LTC4, LTB5, and 6t-LTB5. The crosstalk between ORMDL3 and 5-LO metabolic pathways was supported by the finding that endogenous ORMDL3 and 5-LO are localized in similar endoplasmic reticulum domains in human mast cells and that ORMDL3 physically interacts with 5-LO. Further experiments showed that 5-LO also interacts with the long-chain 1 and long chain 2 subunits of SPT. In agreement with these findings, 5-LO knockdown increased ceramide levels, and silencing of SPTLC1 decreased arachidonic acid metabolism to LTs to levels observed upon 5-LO knockdown. These results demonstrate functional crosstalk between the LT and sphingolipid metabolic pathways, leading to the production of lipid signaling mediators. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2022 Electronic address https://www.jlr.org/article/S0022-2275(21)00103-6/fulltext
Number of the records: 1