Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways

0552089 - ÚMG 2022 RIV US eng J - Článek v odborném periodiku
Bugajev, Viktor - Paulenda, Tomáš - Utekal, Pavol - Mrkáček, Michal - Hálová, Ivana - Kuchař, L. - Kuda, Ondřej - Vávrová, Petra - Schuster, Bjorn - Fuentes-Liso, Sergio - Potůčková, Lucie - Smrž, D. - Černohouzová, Sára - Dráberová, Lubica - Bambousková, Monika - Dráber, Petr
Crosstalk between ORMDL3, serine palmitoyltransferase, and 5-lipoxygenase in the sphingolipid and eicosanoid metabolic pathways.
Journal of Lipid Research. Roč. 62, September (2021), č. článku 100121. ISSN 0022-2275. E-ISSN 1539-7262
Grant CEP: GA ČR GA18-18521S; GA ČR(CZ) GA17-20915S; GA MŠMT ED2.1.00/19.0395; GA MŠMT(CZ) LM2018126; GA MŠMT EF18_046/0015861; GA MŠMT(CZ) LM2018129; GA MŠMT(CZ) EF18_046/0016045
Grant ostatní: AV ČR(CZ) LQ200111901
Program: Prémie Lumina quaeruntur
Institucionální podpora: RVO:68378050 ; RVO:67985823
Klíčová slova: sphingolipids * leukotrienes * immunology * signal transduction * inflammation * peritoneal-derived mast cells * ER membrane domains * lipid mass spectrometry * hplc
Obor OECD: Biochemistry and molecular biology; Biochemistry and molecular biology (FGU-C)
Impakt faktor: 6.676, rok: 2021
Způsob publikování: Open access
https://www.jlr.org/article/S0022-2275(21)00103-6/fulltext

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.
Trvalý link: http://hdl.handle.net/11104/0327239