Format

Send to

Choose Destination
FASEB J. 2015 Jun;29(6):2439-49. doi: 10.1096/fj.14-268474. Epub 2015 Feb 12.

Role of p38 mitogen-activated protein kinase in linking stearoyl-CoA desaturase-1 activity with endoplasmic reticulum homeostasis.

Author information

1
*Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany andreas.koeberle@uni-jena.de.
2
*Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.

Abstract

Endoplasmic reticulum (ER) homeostasis is regulated by a network of signaling pathways to which stearoyl-CoA desaturase (SCD)-1, p38 mitogen-activated protein kinase (MAPK) and the unfolded protein response (UPR) belong. Because all these pathways are located at the interface of cell cycle control and cell stress, we hypothesized a cross-regulation. Interference with SCD-1, either by small interfering (si)RNA or the specific SCD-1 inhibitor CAY10566 (EC₅₀ 1 µM; ≥ 24 h), specifically induced phosphorylation and thus activation of p38 MAPK in NIH-3T3 mouse fibroblasts (1.5- to 2-fold; 48 hours). During lipotoxic and cell cycle stress, prolonged activation of p38 MAPK due to SCD-1 inhibition induced ER stress, the UPR, and ER/Golgi remodeling as shown by Western blot and immunofluorescence microscopy (1.2- to 3.5-fold). Specific inhibition of p38 MAPK by Skepinone-L [half maximal inhibitory concentration (IC₅₀) 25-50 nM] reversed these effects (at 1 µM; 48 hours). The specificity by which SCD-1 modulates the phospholipid composition and inhibits p38 MAPK signaling (among survival/stress pathways), thereby preventing ER stress (but not other SCD-1-dependent responses), suggests selective protein-lipid interactions. Palmitoleoyl/oleoyl-phosphatidylinositol (PI) was accordingly identified as potential lipid mediator using chromatography-coupled ESI tandem mass spectrometry. We conclude that the negative regulation of p38 MAPK mediates the protective effects of SCD-1 on ER homeostasis under distinct stress conditions.

KEYWORDS:

bioactive lipid; fatty acid; lipidomics; phospholipid; unfolded protein response

PMID:
25678624
DOI:
10.1096/fj.14-268474
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center