GTPase蛋白RSA-14-44的功能研究
摘要
精子发生是一个错综复杂且高度有序的动态过程,其间生精干细胞经过有丝分裂、减数分裂、核浓缩、细胞变形、激活等众多复杂的变化,最终发育、分化成为成熟的精子。这些不同的细胞事件既相对独立、相互区别,同时又相互关联、相互衔接,整合成为一个系统、高效并且可控的有机整体。为确保种群的繁衍和物种的进化,生命体逐渐发展出一整套精密、复杂的机制来调节整个精子发生过程。其中一个很重要的方面就是依据不同发育阶段的需要,在时间和空间上对精子发生相关基因的表达进行严密的控制。因此,分离、克隆不同发育阶段的差异表达基因,深入研究它们在精子发生过程中所发挥的作用,对于揭示精子发生机理和促进人类生殖健康均具有重要意义。
在本实验室的前期工作中,我们利用激光捕获显微切割技术(Laser CaptureMicrodissection,LCM),成功地捕获了大鼠的初级精母细胞和圆形精子细胞;通过抑制性消减杂交技术(Suppressive Substractive Hybridization,SSH)构建圆形精子细胞消减初级精母细胞的消减cDNA文库(RSA),并从中筛选出差异表达基因。本研究中所涉及的RSA-14-44/mRSA-14-44就是通过上述筛选所得到的一个新基因,其所对应的原始克隆编号为14-44,因此命名为RSA-14-44。该基因的GenBank登录号为AY149343;编码序列长度为582bp,编码一个由193个氨基酸组成并具有Rho-GTPase保守结构域的蛋白质。
生物信息学分析结果显示,RSA-14-44的氨基酸序列与Rho GTPase家族中的RhoAlike亚家族成员高度同源。同时,我们通过体外实验证实纯化的GST-RSA-14-44蛋白具有GTPase活性。因此,确定RSA-14-44是RhoA like亚家族的一个新成员。
针对RSA-14-44的多组织表达分析结果表明,该基因在大鼠睾丸组织中特异表达。对大鼠睾丸组织的免疫组织化学研究证实,RSA-14-44的表达与精子发生过程密切相关;主要存在于除精原细胞外的各期生精细胞中,特别是处于第一次减数分裂末期的初级精母细胞中。
利用生物信息学数据库进行同源序列比对,在小鼠中找到一个RSA-14-44的同源序列基因4930544G11Rik(GeneID:67653)。二者所编码的蛋白质序列高度同源,相似度达95.3%,并且具有相同的睾丸组织表达特异性。因此,我们确认该基因是RSA-14-44的小鼠同源基因,并将其命名为mRSA-14-44。
在前期工作中,我们利用酵母双杂交技术筛选睾丸组织中可能存在的与RSA-14-44相互作用的蛋白质,结果显示蛋白酶体的组成蛋白PSMB5与RSA-14-44之间存在相互作用。利用GST-pull down的方法,我们证实RSA-14-44与PSMB5之间存在相互作用。同时,我们还构建了mRSA-14-44的真核表达质粒,并通过免疫共沉淀实验验证了mRSA-14-44与PSMB5之间存在相互作用。
为明确RSA-14-44/mRSA-14-44在精子发生过程中的生物学功能,我们首先通过免疫荧光观察RSA-14-44和PSMB5在大鼠精子发生过程中的表达变化。结果显示,二者在分离到的各期生精细胞中共定位,包括次级精母细胞、圆形精子细胞、长形精子细胞和成熟的精子;二者的定位与整个精子发生过程密切相关,随着发育阶段的不同产生相应的变化。其次,蛋白酶体活性实验的结果证实在过表达RSA-14-44/mRSA-14-44或共表达RSA-14-44/mRSA-14-44和PSMB5的情况下,细胞的蛋白酶体活性并未发生显著变化。此外,我们还利用高通量筛选平台对RSA-14-44/mRSA-14-44可能参与的细胞信号传递通路进行鉴定。分析结果显示,除CREB通路外,过表达RSA-14-44/mRSA-14-44对所选定的细胞信号通路并未产生显著的影响。
为进一步明确RSA-14-44/ mRSA-14-44与PSMB5相互作用同RSA-14-44/mRSA-14-44蛋白质结构之间的关系,我们构建了分别针对RSA-14-44/ mRSA-14-44和PSMB5的突变体蛋白表达质粒,并通过免疫共沉淀和甘油密度梯度分离细胞组分来进行相应研究。免疫共沉淀实验结果显示RSA-14-44/ mRSA-14-44与PSMB5之间存在的相互作用并不依赖于RSA-14-44/mRSA-14-44的激活;同时也不依赖于RSA-14-44/mRSA-14-44中的效应蛋白结合区、高可变区结构;但位于CAAX motif的190位Cysteine对维持二者间的相互作用至关重要。结构预测显示RSA-14-44/mRSA-14-44中的C190位点可能存在棕榈酰化(palmitoylation)修饰。
另一方面,利用甘油密度梯度离心分离不同的细胞组分,分析其中RSA-14-44/mRSA-14-44和PSMB5的分布。实验结果表明细胞中的PSMB5以前体形式合成,其N-terminal包含propeptide结构,需要经过自剪切加工移除propeptide,转变为成熟形式的PSMB5;二者存在于不同的细胞组分之中,成熟体形式PSMB5与蛋白酶体的另一个非催化亚单位PSMA7共存于沉降系数较大的细胞组分,前体形式的PSMB5主要与RSA-14-44/mRSA-14-44共存于沉降系数较小的细胞组分。
在上述研究的基础上,我们还进一步探讨了RSA-14-44/ mRSA-14-44对细胞中PSMB5加工过程的影响。分析结果显示,在细胞中共表达RSA-14-44/mRSA-14-44和PSMB5能够相应提高其中前体形式和成熟体形式PSMB5的蛋白质水平,但并不影响前体蛋白的自剪切加工速率。
Spermatogenesis is a complex and continuative progress,during which spermatogenic stem cells differentiated into mature spermatozoa,sequentially undergoing developmental changes including mitosis,meiosis,nucleus condensation and cytoplasm deposition.This progress would be out of control,even fall into serious dysfunction without precisely special and temporal regulation served by sets of mechanisms.As a highly specific pattern of gene expression occurs in spermatogenesis,the identification and study of differentially expressed genes,especially novel genes absent from somatic cells are of great value to delineate the elegant mechanisms regulating spermatogenesis.
In our previous work,some new genes were identified from rat primary spermatocytes cDNA library constructed by suppressive subtractive hybridization(SSH) between cDNAs of laser capture micro-dissection(LCM) trapped rat primary spermatocytes and round spermatids.RSA-14-44 was one of these new genes.Here we show some primary results from exploring the functions of RSA-14-44 in spermatogenesis.
First we got some general information on RSA-14-44 from GenBank with a corresponding GeneID number,AY149343.With an open reading frame of 582bp,RSA-14-44 encodes a 193-amino-acid consisted protein,at the N-terminal of which was included a conserved Rho GTPase domain.As RSA-14-44 shared high similarity in amino sequence with other members of RhoA like superfamily in this domain,it was designated to be a new member of this family,which was confirmed by the data from a GTPase activity assay using the purified recombinant GST-RSA-14-44 and GST proteins.
The expression of RSA-14-44 was exclusive in rat testis and showed a spermatogenesis closely related pattern,which was confirmed by immunohischemial analysis on rat testis sections with specific antibody.Except for spermatogonia,other spermatogeic cell lineages were all the places where RSA-14-44 was expressed.Interestingly,the signal of RSA-14-44 was accumulated in much higher density in pachytene spermatocytes.Meanwhile,a gene, 4930544G11Rik,was identified from mouse by screening the putative homolog of RSA-14-44 in other species,which displayed the same tissue-specificity as RSA-14-44.Due to a high similarity between the sequences of RSA-14-44 and of the protein coded by 4930544G11Rik, 4930544G11Rik was referred as the homolog of RSA-14-44 in mouse with a new name, mRSA-14-44.
In order to elucidate the roles of RSA-14-44 in spermatogenesis,we had screened the possible interactive proteins from testis previously by using yeast two hybridization(Y2H). Several candidates including PSMB5,which is a catalytic subunit of proteasome,were identified.Here the interaction between RSA-14-44 and PSMB5 was confirmed by a GST-pull down assay.Furthermore,we observed this interaction again when we co-immunoprecipitated PSMB5 and mRSA-14-44 from the cells.Fortunately,RSA-14-44 and PSMB5 showed exactly the same pattern of localization in the various spermatogenetic cells existing in different stages of spermatogenesis,which were isolated from seminiferous tubules in rat testis.And just as showed in the results of immunohischemical analyses of rat testis above,these two proteins were both accumulated mainly in the spermatocytes,round spermatids,elongated spermatids and sperms,and their localizations changed according to the progress of spermatogenesis.
However,no significant effect of RSA-14-44/mRSA-14-44 on the activity of proteasome was found after the over-expression of RSA-14-44/mRSA-14-44 or co-expression of RSA-14-44/mRSA-14-44 and PSMB5 in cells.For resolving the conflict between the interaction and the result of proteasome activity assays,we had to clarify the detailed information on the interaction between RSA-14-44/mRSA-14-44 and PSMB5 by constructing mutants of RSA-14-44/mRSA-14-44 and PSMB5 respectively.
It was showed latter that the interaction between RSA-14-44/mRSA-14-44 and PSMB5 was independent of the activation of RSA-14-44/mRSA-14-44 and might not be involved in the structures corresponding to the effectors-binding domain and hypervariable region in RSA-14-44/mRSA-14-44.But the 190th cysteine,a putative site for palmitoylation modification,in the C-terminal of RSA-14-44/mRSA-14-44 was required for this interaction.
On the other hand,PSMB5 was actually synthesized first as a pro-type in the cells,with a propeptide in its N-terminal.After removing the propeptide by autoclevage,this pro-type protein soon turned into a mature type one,which was assembled into proteasome finally.It was notable that RSA-14-44/mRSA-14-44 was associated with neither the mature type PSMB5 nor the proteasome,but with the pro-type PSMB5,which was showed by a gradient sedimentation analysis.By the way,we found that both protein levels of the pro-type and of the mature type PSMB5 were increased when RSA-14-44/mRSA-14-44 was overexpressed in cells and also confirmed that the propeptide was essential for the incorporation of PSMB5 into proteasomes.
Since most members of Rho family act as switches for signal transduction through cycling between GTP-binding and GDP-binding configurations,we investigated the possible effect of RSA-14-44/mRSA-14-44 on the signal transduction by screening a cell signal transduction platform.However,except for in CREB,no significant effect of RSA-14-44/ mRSA-14-44 on the transduction was observed in the selected cellular signaling pathways when RSA-14-44/mRSA-14-44 was overexpressed in the corresponding cell models.
在本实验室的前期工作中,我们利用激光捕获显微切割技术(Laser CaptureMicrodissection,LCM),成功地捕获了大鼠的初级精母细胞和圆形精子细胞;通过抑制性消减杂交技术(Suppressive Substractive Hybridization,SSH)构建圆形精子细胞消减初级精母细胞的消减cDNA文库(RSA),并从中筛选出差异表达基因。本研究中所涉及的RSA-14-44/mRSA-14-44就是通过上述筛选所得到的一个新基因,其所对应的原始克隆编号为14-44,因此命名为RSA-14-44。该基因的GenBank登录号为AY149343;编码序列长度为582bp,编码一个由193个氨基酸组成并具有Rho-GTPase保守结构域的蛋白质。
生物信息学分析结果显示,RSA-14-44的氨基酸序列与Rho GTPase家族中的RhoAlike亚家族成员高度同源。同时,我们通过体外实验证实纯化的GST-RSA-14-44蛋白具有GTPase活性。因此,确定RSA-14-44是RhoA like亚家族的一个新成员。
针对RSA-14-44的多组织表达分析结果表明,该基因在大鼠睾丸组织中特异表达。对大鼠睾丸组织的免疫组织化学研究证实,RSA-14-44的表达与精子发生过程密切相关;主要存在于除精原细胞外的各期生精细胞中,特别是处于第一次减数分裂末期的初级精母细胞中。
利用生物信息学数据库进行同源序列比对,在小鼠中找到一个RSA-14-44的同源序列基因4930544G11Rik(GeneID:67653)。二者所编码的蛋白质序列高度同源,相似度达95.3%,并且具有相同的睾丸组织表达特异性。因此,我们确认该基因是RSA-14-44的小鼠同源基因,并将其命名为mRSA-14-44。
在前期工作中,我们利用酵母双杂交技术筛选睾丸组织中可能存在的与RSA-14-44相互作用的蛋白质,结果显示蛋白酶体的组成蛋白PSMB5与RSA-14-44之间存在相互作用。利用GST-pull down的方法,我们证实RSA-14-44与PSMB5之间存在相互作用。同时,我们还构建了mRSA-14-44的真核表达质粒,并通过免疫共沉淀实验验证了mRSA-14-44与PSMB5之间存在相互作用。
为明确RSA-14-44/mRSA-14-44在精子发生过程中的生物学功能,我们首先通过免疫荧光观察RSA-14-44和PSMB5在大鼠精子发生过程中的表达变化。结果显示,二者在分离到的各期生精细胞中共定位,包括次级精母细胞、圆形精子细胞、长形精子细胞和成熟的精子;二者的定位与整个精子发生过程密切相关,随着发育阶段的不同产生相应的变化。其次,蛋白酶体活性实验的结果证实在过表达RSA-14-44/mRSA-14-44或共表达RSA-14-44/mRSA-14-44和PSMB5的情况下,细胞的蛋白酶体活性并未发生显著变化。此外,我们还利用高通量筛选平台对RSA-14-44/mRSA-14-44可能参与的细胞信号传递通路进行鉴定。分析结果显示,除CREB通路外,过表达RSA-14-44/mRSA-14-44对所选定的细胞信号通路并未产生显著的影响。
为进一步明确RSA-14-44/ mRSA-14-44与PSMB5相互作用同RSA-14-44/mRSA-14-44蛋白质结构之间的关系,我们构建了分别针对RSA-14-44/ mRSA-14-44和PSMB5的突变体蛋白表达质粒,并通过免疫共沉淀和甘油密度梯度分离细胞组分来进行相应研究。免疫共沉淀实验结果显示RSA-14-44/ mRSA-14-44与PSMB5之间存在的相互作用并不依赖于RSA-14-44/mRSA-14-44的激活;同时也不依赖于RSA-14-44/mRSA-14-44中的效应蛋白结合区、高可变区结构;但位于CAAX motif的190位Cysteine对维持二者间的相互作用至关重要。结构预测显示RSA-14-44/mRSA-14-44中的C190位点可能存在棕榈酰化(palmitoylation)修饰。
另一方面,利用甘油密度梯度离心分离不同的细胞组分,分析其中RSA-14-44/mRSA-14-44和PSMB5的分布。实验结果表明细胞中的PSMB5以前体形式合成,其N-terminal包含propeptide结构,需要经过自剪切加工移除propeptide,转变为成熟形式的PSMB5;二者存在于不同的细胞组分之中,成熟体形式PSMB5与蛋白酶体的另一个非催化亚单位PSMA7共存于沉降系数较大的细胞组分,前体形式的PSMB5主要与RSA-14-44/mRSA-14-44共存于沉降系数较小的细胞组分。
在上述研究的基础上,我们还进一步探讨了RSA-14-44/ mRSA-14-44对细胞中PSMB5加工过程的影响。分析结果显示,在细胞中共表达RSA-14-44/mRSA-14-44和PSMB5能够相应提高其中前体形式和成熟体形式PSMB5的蛋白质水平,但并不影响前体蛋白的自剪切加工速率。
Spermatogenesis is a complex and continuative progress,during which spermatogenic stem cells differentiated into mature spermatozoa,sequentially undergoing developmental changes including mitosis,meiosis,nucleus condensation and cytoplasm deposition.This progress would be out of control,even fall into serious dysfunction without precisely special and temporal regulation served by sets of mechanisms.As a highly specific pattern of gene expression occurs in spermatogenesis,the identification and study of differentially expressed genes,especially novel genes absent from somatic cells are of great value to delineate the elegant mechanisms regulating spermatogenesis.
In our previous work,some new genes were identified from rat primary spermatocytes cDNA library constructed by suppressive subtractive hybridization(SSH) between cDNAs of laser capture micro-dissection(LCM) trapped rat primary spermatocytes and round spermatids.RSA-14-44 was one of these new genes.Here we show some primary results from exploring the functions of RSA-14-44 in spermatogenesis.
First we got some general information on RSA-14-44 from GenBank with a corresponding GeneID number,AY149343.With an open reading frame of 582bp,RSA-14-44 encodes a 193-amino-acid consisted protein,at the N-terminal of which was included a conserved Rho GTPase domain.As RSA-14-44 shared high similarity in amino sequence with other members of RhoA like superfamily in this domain,it was designated to be a new member of this family,which was confirmed by the data from a GTPase activity assay using the purified recombinant GST-RSA-14-44 and GST proteins.
The expression of RSA-14-44 was exclusive in rat testis and showed a spermatogenesis closely related pattern,which was confirmed by immunohischemial analysis on rat testis sections with specific antibody.Except for spermatogonia,other spermatogeic cell lineages were all the places where RSA-14-44 was expressed.Interestingly,the signal of RSA-14-44 was accumulated in much higher density in pachytene spermatocytes.Meanwhile,a gene, 4930544G11Rik,was identified from mouse by screening the putative homolog of RSA-14-44 in other species,which displayed the same tissue-specificity as RSA-14-44.Due to a high similarity between the sequences of RSA-14-44 and of the protein coded by 4930544G11Rik, 4930544G11Rik was referred as the homolog of RSA-14-44 in mouse with a new name, mRSA-14-44.
In order to elucidate the roles of RSA-14-44 in spermatogenesis,we had screened the possible interactive proteins from testis previously by using yeast two hybridization(Y2H). Several candidates including PSMB5,which is a catalytic subunit of proteasome,were identified.Here the interaction between RSA-14-44 and PSMB5 was confirmed by a GST-pull down assay.Furthermore,we observed this interaction again when we co-immunoprecipitated PSMB5 and mRSA-14-44 from the cells.Fortunately,RSA-14-44 and PSMB5 showed exactly the same pattern of localization in the various spermatogenetic cells existing in different stages of spermatogenesis,which were isolated from seminiferous tubules in rat testis.And just as showed in the results of immunohischemical analyses of rat testis above,these two proteins were both accumulated mainly in the spermatocytes,round spermatids,elongated spermatids and sperms,and their localizations changed according to the progress of spermatogenesis.
However,no significant effect of RSA-14-44/mRSA-14-44 on the activity of proteasome was found after the over-expression of RSA-14-44/mRSA-14-44 or co-expression of RSA-14-44/mRSA-14-44 and PSMB5 in cells.For resolving the conflict between the interaction and the result of proteasome activity assays,we had to clarify the detailed information on the interaction between RSA-14-44/mRSA-14-44 and PSMB5 by constructing mutants of RSA-14-44/mRSA-14-44 and PSMB5 respectively.
It was showed latter that the interaction between RSA-14-44/mRSA-14-44 and PSMB5 was independent of the activation of RSA-14-44/mRSA-14-44 and might not be involved in the structures corresponding to the effectors-binding domain and hypervariable region in RSA-14-44/mRSA-14-44.But the 190th cysteine,a putative site for palmitoylation modification,in the C-terminal of RSA-14-44/mRSA-14-44 was required for this interaction.
On the other hand,PSMB5 was actually synthesized first as a pro-type in the cells,with a propeptide in its N-terminal.After removing the propeptide by autoclevage,this pro-type protein soon turned into a mature type one,which was assembled into proteasome finally.It was notable that RSA-14-44/mRSA-14-44 was associated with neither the mature type PSMB5 nor the proteasome,but with the pro-type PSMB5,which was showed by a gradient sedimentation analysis.By the way,we found that both protein levels of the pro-type and of the mature type PSMB5 were increased when RSA-14-44/mRSA-14-44 was overexpressed in cells and also confirmed that the propeptide was essential for the incorporation of PSMB5 into proteasomes.
Since most members of Rho family act as switches for signal transduction through cycling between GTP-binding and GDP-binding configurations,we investigated the possible effect of RSA-14-44/mRSA-14-44 on the signal transduction by screening a cell signal transduction platform.However,except for in CREB,no significant effect of RSA-14-44/ mRSA-14-44 on the transduction was observed in the selected cellular signaling pathways when RSA-14-44/mRSA-14-44 was overexpressed in the corresponding cell models.
引文
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