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

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.