中科院刘勇课题组发现调节胰岛素生成新机制
中科院上海生命科学研究院营养科学研究所刘勇小组在最新研究中，揭示了一种被称为的信号调节蛋白在胰岛素生成中具有调控作用，同时发现这一调节机制在从低等动物果蝇到哺乳动物的进化过程中具有高度的保守性。近日，相关研究论文在线发表在国际学术期刊《分子与细胞生物学》上。
胰岛素合成与分泌以及胰岛素敏感性的异常改变，是导致糖尿病发生发展的重要因素。因此，深入了解胰岛素合成方面复杂的调控机制对于解析糖尿病发生的生物学基础具有非常重要的意义。
“此项研究就是利用果蝇模式系统，发现了泛素连接酶Cbl参与了胰岛素合成的调控过程。”刘勇介绍说。
Cbl（Casitas B-lineage Lymphoma，简称Cbl）是一类拥有E3泛素连接酶活性的胞内信号接头蛋白（Adaptor），可以通过与其他蛋白质分子结合，参与多种细胞信号转导的调控过程。然而，哺乳动物中的Cbl蛋白在能量平衡与糖脂代谢调节方面所扮演的具体角色迄今尚不明了。
调节胰岛素生成新机制
为探寻Cbl蛋白在代谢平衡中的作用机制，营养所博士研究生于月等在研究员刘勇的指导下，以果蝇作为研究模型，通过一系列生理学和遗传学的研究方法，发现在果蝇神经系统以及特定产生胰岛素的神经细胞中，Cbl的缺失导致胰岛素样肽的表达显著增强、淋巴液中葡萄糖含量下降、寿命缩短，同时使果蝇对饥饿与氧化应激刺激更为敏感。
进一步的遗传互作实验显示，Cbl能够通过调节一定信号通路影响果蝇中胰岛素样肽的表达。刘勇表示：“这一调节机制还在大鼠产生胰岛素的胰岛细胞中得到验证。”
相关专家认为，这些研究结果揭示了胰岛素合成过程中一个前所未知的重要调控机制，为进一步阐明Cbl蛋白家族在生长代谢、细胞应激和寿命调节等方面的作用提供了新的线索，也为了解胰岛素合成的调节异常提供了新视角。
据悉，该项研究得到国家科技部、国家自然科学基金委、上海市科委及中科院等的支持。
Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster
Yue Yua, Ying Suna, Shengqi Hea, Cheng Yana, Liangyou Ruib, Wenjun Lia and Yong Liua
The Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-like peptides (dILPs) in the brain. We found that dCbl was highly expressed in the brain and knockdown of the expression of dCbl specifically in neurons by RNA interference increased sensitivity to oxidative stress or starvation, decreased carbohydrate levels, and shortened life span. Insulin-producing neuron-specific knockdown of dCbl resulted in similar phenotypes. dCbl deficiency in either the brain or insulin-producing cells upregulated the expression of dilp genes, resulting in elevated activation of the dILP pathway, including phosphorylation of Drosophila Akt and Drosophila extracellular signal-regulated kinase (dERK). Genetic interaction analyses revealed that blocking Drosophila epidermal growth factor receptor (dEGFR)-dERK signaling in pan-neurons or insulin-producing cells by overexpressing a dominant-negative form of dEGFR abolished the effect of dCbl deficiency on the upregulation of dilp genes. Furthermore, knockdown of c-Cbl in INS-1 cells, a rat β-cell line, also increased insulin biosynthesis and glucose-stimulated secretion in an ERK-dependent manner. Collectively, these results suggest that neuronal dCbl regulates life span, stress responses, and metabolism by suppressing dILP production and the EGFR-ERK pathway mediates the dCbl action. Cbl suppression of insulin biosynthesis is evolutionarily conserved, raising the possibility that Cbl may similarly exert its physiological actions through regulating insulin production in β cells
文献链接：Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster
