Role of stearoyl-CoA desaturase-1 for the regulation of ER homeostasis by stearoyl-CoA desaturase-1

• Applicant: Professor Dr. Andreas Koeberle
• Subject Area: Biochemistry
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261036519

Stearoyl-CoA desaturase (SCD)-1 converts saturated to monounsaturated fatty acids (MUFAs) and is a key enzyme for metabolic diseases and cancer. Despite intensive research, the signaling pathways downstream of SCD-1 are not fully understood, and possibly involved metabolites incompletely defined. We hypothesized a co-regulation of SCD-1 and stress-activated protein kinases because both are located at the interface of cell cycle control and cell stress. In fact, our preliminary work shows that p38 mitogen-activated protein kinase (MAPK) - a regulator of cell growth and cell stress - is activated by specific inhibition of SCD-1. Activation of p38 MAPK is coupled to the unfolded protein response (UPR) - a signaling cascade activated by ER stress aiming to maintain ER homeostasis. The activation of the UPR following SCD-1 inhibition was prevented by the highly specific p38 MAPK inhibitor Skepinone-L (Koeberle et al., 2011, Nat. Chem. Biol.), while other cellular processes (e.g., glucose uptake) were not affected, indicating a specific signal transmission. The requested project shall confirm the novel regulatory link between SCD-1, p38 MAPK and the UPR and investigate the specificity and physiological relevance of this network. Regarding the central role of the ER in linking stress, metabolism and survival, the regulation of ER homeostasis by SCD-1 through p38 MAPK might critically contribute to the stress-preventive and tumor-promoting activities of SCD-1. Based on these findings, the mechanism underlying the activation of p38 MAPK by inhibition of SCD-1 shall be addressed. The only moderate effect of SCD-1 inhibition on membrane desaturation together with the apparent specificity of the signaling cascade let us speculate that not broad membrane effects but intermediary formed bioactive SCD-1 metabolites regulate p38 MAPK. In fact, one of our previous studies shows that the proportion of distinct membrane lipids correlates with the mitogenic effect of MUFAs (Koeberle et al., 2012, J. Biol. Chem.). We hypothesize also here a role of membrane lipids as regulators of p38 MAPK. The experimental confirmation of their transducer function in this study would place the signal transduction of SCD-1 in a different light.

• DFG Programme: Research Grants