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

硬脂酰辅酶A脱饱和酶(SCD-1)能将饱和脂肪酸转化为单不饱和脂肪酸(MUFAs)，是代谢疾病和癌症的关键酶。尽管进行了大量的研究，但SCD-1下游的信号通路还不完全清楚，可能涉及的代谢物也不完全确定。我们假设了SCD-1和压力激活蛋白激酶的共同调节，因为它们都位于细胞周期控制和细胞应激的交界处。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-通过对SCD-1的特异性抑制而激活。P38MAPK的激活与未折叠蛋白反应(UPR)相耦合，UPR是内质网应激激活的一个信号级联反应，旨在维持内质网内稳态。高度特异的p38 MAPK抑制剂Skepinone-L(Koeberle等人，2011年，NAT)阻止了SCD-1抑制后UPR的激活。化学。生物)，而其他细胞过程(例如，葡萄糖吸收)不受影响，这表明特定的信号传递。所要求的项目应确认SCD-1、p38 MAPK和UPR之间的新的调控联系，并调查该网络的特异性和生理相关性。关于内质网在连接应激、代谢和生存中的中心作用，SCD-1通过p38MAPK调节内质网稳态可能对SCD-1的应激预防和促肿瘤活性起关键作用。基于这些发现，应探讨抑制SCD-1激活p38 MAPK的机制。SCD-1抑制细胞膜去饱和的唯一温和作用，以及信号级联的明显特异性，使我们推测，不是广泛的膜效应，而是中介形成的生物活性SCD-1代谢产物调节p38MAPK。事实上，我们之前的一项研究表明，不同的膜脂比例与MUFAs的促分裂作用有关(Koeberle等人，2012，J.Biol。化学)。我们在这里还假设了膜脂作为p38MAPK的调节因子。在这项研究中，对它们的转导功能的实验证实将把SCD-1的信号转导放在不同的角度。

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.