核糖体蛋白RPS8对蛋白质翻译的影响及其机制的研究
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摘要
Cyclin-dependent kinase 11(CDK11)蛋白家族,即PITSLRE蛋白激酶家族,是一类丝／苏氨酸蛋白激酶,其功能与细胞周期调控、肿瘤的发生以及细胞凋亡相关。研究发现,细胞在发生凋亡过程时,全长的CDK11p110或者CDK11p58被caspase剪切,产生一个分子量大小约46-50 kDa的蛋白,含有CDKll蛋白羧基端的激酶活性区域。进一步研究发现CDKl 1p46在细胞凋亡中发挥重要的作用,但具体机制尚不明确。
我们通过His pull-down联合质谱分析发现核糖体小亚基蛋白S8(RPS8)为CDK11p46相互作用蛋白。GST pull-down和免疫共沉淀实验验证了CDK11p46和RPS8在体外与体内均存在相互作用,免疫荧光共聚焦分析也揭示了它们在细细胞核内存在共定位。体外激酶实验发现,RPS8并不是CDK11p46的底物。进一步的功能研究表明,CDK11p46和RPS8协同抑制帽依赖(cap-dependent)以及帽非依赖(IRES-dependent)的蛋白质翻译,并且协同提高了细胞对于Fas配体诱导凋亡的敏感性。我们的研究为进一步的CDK11p46在调控蛋白质翻译和细胞凋亡中的机制研究奠定了基础。
近年来,蛋白质翻译调控越来越受到关注,其在细胞生长、肿瘤发生以及细胞凋亡中起着中心调节作用,但具体的作用机制尚不明确。核糖体是蛋白质合成的场所,由核糖体蛋白及rRNA组成的复合物。研究发现,核糖体蛋白以及相关翻译因子在蛋白质翻译调控中起到关键的作用。其中,这些调节蛋白的磷酸化修饰,往往调控着这些蛋白的功能。
在第一部分的研究中,我们发现RPS8能够抑制帽依赖以及帽非依赖的蛋白质翻译。我们进一步利用在线软件Scansite预测了RPS8可能的磷酸化位点,并构建了一系列磷酸化位点缺失突变体和模拟磷酸化突变体。通过荧光素酶报告基因活性检测,发现RPS8的T130位点的磷酸化对蛋白质翻译有影响。通过Genedoc软件进行同源比对发现T130位点在哺乳动物以及线虫中保守,GPS2.1软件分析提示了RPS8的T130位点可能的磷酸化激酶,为进一步的RPS8在蛋白质翻译中的功能研究奠定了基础。
Cyclin-dependent kinase 11 (CDK11) isoforms are members of the PITSLRE kinase superfamily and closely related to cell cycle regulation, oncogenesis, and apoptosis.During apoptosis, CDK11p110 and CDK11p58 are cleaved by caspases to generate a smaller 46-50 kDa protein which contains the catalytic kinase domain in the C-terminus of CDK11.CDK11p46 was demonstrated to play an important role in cell apoptosis. However, how CDK11p46 exactly promotes apoptosis is unclear.
By using His pull-down and mass spectrometry analysis, we identified the ribosomal protein S8 (RPS8), a member of the small subunit ribosome, as an interacting partner of CDKllp46. Further analysis confirmed the association of CDK11p46 and RPS8 in vitro and in vivo, and revealed that RPS8 was not a substrate of CDK11p46. Moreover, RPS8 and CDKllp46 synergize to inhibit the translation process both in cap-and internal ribosomal entry site (IRES)-dependent way, and sensitize cells to Fas ligand-induced apoptosis. Taken together, our results provide evidence for the novel role of CDKllp46 in the regulation of translation and cell apoptosis.
It is becoming increasingly evident that the regulation of translation plays a central regulatory role in cell growth, tumorigenesis and cell apoptosis. However the specific mechanism of translation control remains unclear. Ribosome is the component of cell that creates proteins from all amino acids and RNA representing the protein. It is composed of ribosomal proteins and rRNA. Studies have showed that ribosomal proteins and translation factors play a key role in regulation of protein synthesis. More importantly, the phosphorylation of these regulators usually regulates the function of these proteins.
In part I, we found that RPS8 inhibited cap-dependent and cap-independent translation. We further predicted the potential phosphorylation sites of RPS8 by using the Scansite online software. Next, we constructed a series of phosphorylation site mutant which mimic the dephosphorylated or phosphorylated form of RPS8. By luciferase reporter gene assay, we found that the phosphorylation of T130 phosphorylation site of RPS8 may contribute to translation. Homology comparison was performed by Genedoc software and showed that T130 site is highly conserved in Mammalia and C. elegans. GPS2.1 software analysis suggested potential kinase of T130 site. Our research helps to further investigate the mechanism of RPS8 in translational regulation.
我们通过His pull-down联合质谱分析发现核糖体小亚基蛋白S8(RPS8)为CDK11p46相互作用蛋白。GST pull-down和免疫共沉淀实验验证了CDK11p46和RPS8在体外与体内均存在相互作用,免疫荧光共聚焦分析也揭示了它们在细细胞核内存在共定位。体外激酶实验发现,RPS8并不是CDK11p46的底物。进一步的功能研究表明,CDK11p46和RPS8协同抑制帽依赖(cap-dependent)以及帽非依赖(IRES-dependent)的蛋白质翻译,并且协同提高了细胞对于Fas配体诱导凋亡的敏感性。我们的研究为进一步的CDK11p46在调控蛋白质翻译和细胞凋亡中的机制研究奠定了基础。
近年来,蛋白质翻译调控越来越受到关注,其在细胞生长、肿瘤发生以及细胞凋亡中起着中心调节作用,但具体的作用机制尚不明确。核糖体是蛋白质合成的场所,由核糖体蛋白及rRNA组成的复合物。研究发现,核糖体蛋白以及相关翻译因子在蛋白质翻译调控中起到关键的作用。其中,这些调节蛋白的磷酸化修饰,往往调控着这些蛋白的功能。
在第一部分的研究中,我们发现RPS8能够抑制帽依赖以及帽非依赖的蛋白质翻译。我们进一步利用在线软件Scansite预测了RPS8可能的磷酸化位点,并构建了一系列磷酸化位点缺失突变体和模拟磷酸化突变体。通过荧光素酶报告基因活性检测,发现RPS8的T130位点的磷酸化对蛋白质翻译有影响。通过Genedoc软件进行同源比对发现T130位点在哺乳动物以及线虫中保守,GPS2.1软件分析提示了RPS8的T130位点可能的磷酸化激酶,为进一步的RPS8在蛋白质翻译中的功能研究奠定了基础。
Cyclin-dependent kinase 11 (CDK11) isoforms are members of the PITSLRE kinase superfamily and closely related to cell cycle regulation, oncogenesis, and apoptosis.During apoptosis, CDK11p110 and CDK11p58 are cleaved by caspases to generate a smaller 46-50 kDa protein which contains the catalytic kinase domain in the C-terminus of CDK11.CDK11p46 was demonstrated to play an important role in cell apoptosis. However, how CDK11p46 exactly promotes apoptosis is unclear.
By using His pull-down and mass spectrometry analysis, we identified the ribosomal protein S8 (RPS8), a member of the small subunit ribosome, as an interacting partner of CDKllp46. Further analysis confirmed the association of CDK11p46 and RPS8 in vitro and in vivo, and revealed that RPS8 was not a substrate of CDK11p46. Moreover, RPS8 and CDKllp46 synergize to inhibit the translation process both in cap-and internal ribosomal entry site (IRES)-dependent way, and sensitize cells to Fas ligand-induced apoptosis. Taken together, our results provide evidence for the novel role of CDKllp46 in the regulation of translation and cell apoptosis.
It is becoming increasingly evident that the regulation of translation plays a central regulatory role in cell growth, tumorigenesis and cell apoptosis. However the specific mechanism of translation control remains unclear. Ribosome is the component of cell that creates proteins from all amino acids and RNA representing the protein. It is composed of ribosomal proteins and rRNA. Studies have showed that ribosomal proteins and translation factors play a key role in regulation of protein synthesis. More importantly, the phosphorylation of these regulators usually regulates the function of these proteins.
In part I, we found that RPS8 inhibited cap-dependent and cap-independent translation. We further predicted the potential phosphorylation sites of RPS8 by using the Scansite online software. Next, we constructed a series of phosphorylation site mutant which mimic the dephosphorylated or phosphorylated form of RPS8. By luciferase reporter gene assay, we found that the phosphorylation of T130 phosphorylation site of RPS8 may contribute to translation. Homology comparison was performed by Genedoc software and showed that T130 site is highly conserved in Mammalia and C. elegans. GPS2.1 software analysis suggested potential kinase of T130 site. Our research helps to further investigate the mechanism of RPS8 in translational regulation.
引文
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