昆虫CREB激活机制及Arrestin蛋白功能的研究
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摘要
cAMP响应元件(CRE)及其结合蛋白(CREB)在G蛋白偶联受体信号通路中发挥着至关重要的作用,影响着精子发生、记忆形成以及生物节律等多项生理功能。PKA对CREB的133位丝氨酸的磷酸化修饰,使得CREB可以招募CBP/p300等辅激活子以及通用的转录因子,通过RNA聚合酶Ⅱ组建转录起始复合体,增强CRE驱动的下游基因的转录。CRE元件驱动报告基因表达已经成为常用的cAMP检测方法,但是哺乳动物细胞中常用的pCRE-luc载体在昆虫细胞中不能响应cAMP的变化。本文通过启动子替换构建了适合于鳞翅目昆虫细胞的pCRE-luciferase报告基因载体,检测发现Gs隅联的家蚕脂动激素受体(AKHR)和Corazonin受体可以激活CRE驱动的报告基因的表达,但是常用的腺苷酸环化酶激动剂forskloin却未能增强CRE的转录活性。进一步研究发现,胞内钙流变化在CRE激活过程中发挥决定性作用。有趣的是,以PKC特异的抑制剂处理后显著地增强了AKH1激发的CRE驱动的转录,并且PKC的激动剂PMA可以阻断这一效应；而钙调蛋白磷酸酶PP2B的抑制剂却强烈的抑制了CRE驱动的萤光素酶的表达。由此推测昆虫细胞中,PKC组成性的抑制CRE驱动的转录,而PP2B对CREB的去磷酸化是CREB激活转录所必需的。此外,抑制胞外信号调节激酶(ERK)的磷酸化对CRE的转录活性没有显著的影响。
顾名思义,Arrestin蛋白的作用是限制受体的活性,这一特性已成为重要的GPCR信号通路及配体筛选研究方法。Arrestin蛋白分视觉相关和非视觉相关两大类。视觉相关Arrestin蛋白主要在视紫红质受体的脱敏过程中发挥作用,而非视觉相关Arrestin蛋白(β-arrestin1/2)作为重要的支架蛋白,分布更为广泛,除了限制激动剂对受体的活化外,还参与受体的内吞、胞外信号调节激酶的活化、RhoA/ROCK通路、白细胞介素和肿瘤坏死因子的合成以及转录因子NF-κB的激活等多个依赖或J依赖于GPCR的信号通路的调控。本文以果蝇非视觉相关△rrestin蛋白一—Kurtz为模板,通过EST序列拼接结合RACE技术克隆了家蚕非视觉相关△rrestion蛋白,参考果蝇的同源蛋白,命名为BmKurtz。序列相似性分析发现,该蛋白具有典型的非视觉相关Arrestin蛋白结构域；荧光定量PCR显示该蛋白在家蚕五龄幼虫的各个组织中均有表达；激动剂激活的AKHR可以招募该蛋白,说明其参与GPCR信号通路的调控;过表达该蛋白也显著的延迟了ERK的磷酸化,这一点与果蝇的Kurtz蛋白也是类似的。
本研究利用CRE元件构建了适合于鳞翅目昆虫细胞的GPCR信号通路检测系统,并初步揭示了家蚕CREB激活的调控机制。家蚕非视觉相关Arrestin蛋白——Kurtz的克隆与功能鉴定,使其成为昆虫GPCR信号通路的检测方法的重要补充。
The cAMP response element-binding protein, CREB, is a GPCR signal activated transcription factor implicated in the control of many biological processes, such as spermatogenesis, memory and circadian rhythms. CREB is phosphorylated at serine residue133by cAMP-dependent protein kinase A, resulting in initiation of transcription of CREB target genes by recruiting the coactivators CBP or p300that associate with the RNA polymerase Ⅱ complexes. CRE-driven luciferase expression has been widely used to detect the cAMP elevation, but the vector used in mammalian cell is not suitable for insect cells. In the current study, a CRE-driven luciferase assay system was constructed for GPCR characterization in insect cells, our data indicated that Bombyx Gs-coupled adipokinetic hormone receptor and corazonin receptor could effectively initiate CRE-driven luciferase transcription, but forskolin, a reagent to be widely used for activating adenylyl cyclase in mammalian system, failed to induce CRE-driven luciferase expression in insect cells transfected with a CRE-driven reporter construct. Further investigation revealed that PKC specific inhibitor exhibited stimulatory effect on the CRE-driven reporter transcription, whereas blockade of Ca2+signal and inhibition of Ca2+-dependent calcineurin resulted in a significant decrease on the expression of luciferase in insect cells. These results suggest that PKC is likely as a negative regulator to modulate CREB activation, in contrast, other than PK.A, Ca2+signal and Ca2+-dependent calcineurin also essentially contribute to the positive regulation of CREB activity. In addition, the extracellular signal-regulated kinase (ERK) has no significant effect on CRE-driven luciferase expression.
As their names imply, Arrestins "arrest" the agonist to activate GPCR. This belrivor has been widely applied to GPCR signaling detection and ligand screening. Artestins are divided into two groups:visual arrestins turn off the Rhodopsin signaling specilicly, while as important scaffold protein, the non-visual arrestins (β-aneslin1/2) ate distributed more widely and related to receptor internalization, ERK phosphorylation. Rho/ROCK signaling, interleukins/tumor necrosis factor production, activation of NF-κB and so on, besides GPCR desensitization. Referring to non-visual arrest in of Drosophila melanogaster, DmKurtz, we obtained the cDNA sequence containing a coding sequence of kurtz of Bomhyx mori by ESTs (expression sequence tags) splicing and RACE (rapid amplification of cDNA ends) and named after DmKurlz. Sequence alignment showed that BmKurtz contained the non-visual arrestin specific domains, and the result of real-time PCR demonstrated that BmKurtz was distributed widely in5th instar day-3larvae. Furthermore, just like DmKurtz, the BmKurtz could also be recruited by activated AKHR, and the ERK phosphorylation was delayed significantly by over-expression of BmKurtz.
Here we modified the CRE-Luc vector and to make it suitable for GPCR signaling in lepidopteran cell lines. Furthermore, our study shed new light on the underlying molecular mechanism by which CREB activation is regulated in insect. The identification of BmKurtz is an important supplement of GPCR signaling detection system.
顾名思义,Arrestin蛋白的作用是限制受体的活性,这一特性已成为重要的GPCR信号通路及配体筛选研究方法。Arrestin蛋白分视觉相关和非视觉相关两大类。视觉相关Arrestin蛋白主要在视紫红质受体的脱敏过程中发挥作用,而非视觉相关Arrestin蛋白(β-arrestin1/2)作为重要的支架蛋白,分布更为广泛,除了限制激动剂对受体的活化外,还参与受体的内吞、胞外信号调节激酶的活化、RhoA/ROCK通路、白细胞介素和肿瘤坏死因子的合成以及转录因子NF-κB的激活等多个依赖或J依赖于GPCR的信号通路的调控。本文以果蝇非视觉相关△rrestin蛋白一—Kurtz为模板,通过EST序列拼接结合RACE技术克隆了家蚕非视觉相关△rrestion蛋白,参考果蝇的同源蛋白,命名为BmKurtz。序列相似性分析发现,该蛋白具有典型的非视觉相关Arrestin蛋白结构域；荧光定量PCR显示该蛋白在家蚕五龄幼虫的各个组织中均有表达；激动剂激活的AKHR可以招募该蛋白,说明其参与GPCR信号通路的调控;过表达该蛋白也显著的延迟了ERK的磷酸化,这一点与果蝇的Kurtz蛋白也是类似的。
本研究利用CRE元件构建了适合于鳞翅目昆虫细胞的GPCR信号通路检测系统,并初步揭示了家蚕CREB激活的调控机制。家蚕非视觉相关Arrestin蛋白——Kurtz的克隆与功能鉴定,使其成为昆虫GPCR信号通路的检测方法的重要补充。
The cAMP response element-binding protein, CREB, is a GPCR signal activated transcription factor implicated in the control of many biological processes, such as spermatogenesis, memory and circadian rhythms. CREB is phosphorylated at serine residue133by cAMP-dependent protein kinase A, resulting in initiation of transcription of CREB target genes by recruiting the coactivators CBP or p300that associate with the RNA polymerase Ⅱ complexes. CRE-driven luciferase expression has been widely used to detect the cAMP elevation, but the vector used in mammalian cell is not suitable for insect cells. In the current study, a CRE-driven luciferase assay system was constructed for GPCR characterization in insect cells, our data indicated that Bombyx Gs-coupled adipokinetic hormone receptor and corazonin receptor could effectively initiate CRE-driven luciferase transcription, but forskolin, a reagent to be widely used for activating adenylyl cyclase in mammalian system, failed to induce CRE-driven luciferase expression in insect cells transfected with a CRE-driven reporter construct. Further investigation revealed that PKC specific inhibitor exhibited stimulatory effect on the CRE-driven reporter transcription, whereas blockade of Ca2+signal and inhibition of Ca2+-dependent calcineurin resulted in a significant decrease on the expression of luciferase in insect cells. These results suggest that PKC is likely as a negative regulator to modulate CREB activation, in contrast, other than PK.A, Ca2+signal and Ca2+-dependent calcineurin also essentially contribute to the positive regulation of CREB activity. In addition, the extracellular signal-regulated kinase (ERK) has no significant effect on CRE-driven luciferase expression.
As their names imply, Arrestins "arrest" the agonist to activate GPCR. This belrivor has been widely applied to GPCR signaling detection and ligand screening. Artestins are divided into two groups:visual arrestins turn off the Rhodopsin signaling specilicly, while as important scaffold protein, the non-visual arrestins (β-aneslin1/2) ate distributed more widely and related to receptor internalization, ERK phosphorylation. Rho/ROCK signaling, interleukins/tumor necrosis factor production, activation of NF-κB and so on, besides GPCR desensitization. Referring to non-visual arrest in of Drosophila melanogaster, DmKurtz, we obtained the cDNA sequence containing a coding sequence of kurtz of Bomhyx mori by ESTs (expression sequence tags) splicing and RACE (rapid amplification of cDNA ends) and named after DmKurlz. Sequence alignment showed that BmKurtz contained the non-visual arrestin specific domains, and the result of real-time PCR demonstrated that BmKurtz was distributed widely in5th instar day-3larvae. Furthermore, just like DmKurtz, the BmKurtz could also be recruited by activated AKHR, and the ERK phosphorylation was delayed significantly by over-expression of BmKurtz.
Here we modified the CRE-Luc vector and to make it suitable for GPCR signaling in lepidopteran cell lines. Furthermore, our study shed new light on the underlying molecular mechanism by which CREB activation is regulated in insect. The identification of BmKurtz is an important supplement of GPCR signaling detection system.
引文
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