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

硬脂酰辅酶A去饱和酶（SCD）-1将饱和脂肪酸转化为单不饱和脂肪酸（MUFA），是代谢疾病和癌症的关键酶。尽管进行了深入的研究，但SCD-1下游的信号通路尚未完全了解，可能涉及的代谢物也未完全确定。我们假设SCD-1和应激激活蛋白激酶的共同调节，因为两者都位于细胞周期控制和细胞应激的界面。事实上，我们的初步工作表明，p38丝裂原活化蛋白激酶（MAPK）-细胞生长和细胞应激的调节因子-通过特异性抑制SCD-1而激活。p38 MAPK的激活与未折叠蛋白反应（UPR）偶联，未折叠蛋白反应是由ER应激激活的信号级联，旨在维持ER稳态。通过高度特异性的p38 MAPK抑制剂Skepinone-L防止SCD-1抑制后UPR的活化（Koeberle等人，2011，Nat. Chem. Biol.），而其它细胞过程（例如，葡萄糖摄取）不受影响，表明特异性信号传递。申请的项目应确认SCD-1、p38 MAPK和UPR之间的新型调控联系，并研究该网络的特异性和生理相关性。关于ER在连接应激、代谢和存活中的中心作用，SCD-1通过p38 MAPK调节ER稳态可能对SCD-1的应激预防和肿瘤促进活性有重要贡献。基于这些发现，通过抑制SCD-1来激活p38 MAPK的潜在机制将得到解决。SCD-1抑制对膜去饱和的仅有的中等作用以及信号级联的明显特异性使我们推测，不是广泛的膜作用而是中间形成的生物活性SCD-1代谢物调节p38 MAPK。事实上，我们先前的一项研究表明，不同膜脂质的比例与MUFA的促有丝分裂作用相关（Koeberle等人，2012，J. Biol. Chem.）。我们还假设膜脂质作为p38 MAPK的调节剂的作用。本研究中对它们的转导功能的实验确认将从不同的角度看待SCD-1的信号转导。

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.