鞘氨醇激酶-1的乙酰化修饰及在糖尿病防治中的作用研究
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摘要
鞘氨醇激酶1（Sphingosine Kinase1）SPK1是鞘磷脂代谢中的关键酶，参与了多种细胞生命活动。对SPK1的蛋白序列进行分析发现，其N-端含有一个保守的GKGK结构域，该结构域出现在多种发生乙酰化修饰的蛋白序列中，是一个公认的乙酰化修饰结构域，其中的K是发生乙酰化修饰的位点。据此，推断SPK1可能发生乙酰化修饰。首先，将Flag-SPK1转染到HEK293细胞，用Flag-M2珠子将SPK1沉淀下来，用抗ace-Lys抗体杂交，检测到乙酰化的SPK1。其次，沉淀产物与p300及乙酰CoA共同孵育后用抗ace-Lys抗体杂交，结果显示p300能增强SPK1的乙酰化。以上结果说明SPK1是一个乙酰化修饰蛋白，可被p300乙酰化。将SPK1蛋白GKGK结构域中的两个K均突变为R或Q，并转染HEK293细胞，经G418筛选后获得稳定表达野生型W-SPK1及突变体R-SPK1、Q-SPK1蛋白的细胞系。我们发现稳定表达W-SPK1的细胞检测到SPK1蛋白的乙酰化，而R-SPK1没有检测到乙酰化，揭示SPK1乙酰化发生在其GK结构域的K上。
SPK1蛋白的这种翻译后修饰可能是其蛋白功能的一种重要的调控方式。实验结果表明，SPK1乙酰化修饰后其稳定性增强；将GKGK结构域中的两个K突变为R或Q，封闭了SPK1的泛素化修饰，避免了被蛋白酶体降解。细胞形态上，稳定表达Q-SPK1的细胞与表达W-SPK1及R-SPK1的细胞相比体积变大，但细胞生长速度变慢；流式分析细胞周期发现，稳定表达Q-SPK1的细胞处于S期的细胞明显增多，G2期的则减少，表明Q-SPK1阻断细胞由S期向G2/M期的进程。综上，SPK1乙酰化在调控细胞生长、大小及细胞周期中有重要作用。
在体外实验基础上，以自发性2型糖尿病KK/Ay小鼠为动物模型，灌胃给予携带野生型及突变体spk1基因的减毒沙门氏菌，在动物整体水平评价SPK1乙酰化修饰对糖尿病动物血糖的调节作用。结果显示，口服携带Q-SPK1质粒的减毒沙门氏菌可以降低2型糖尿病小鼠KK/Ay的血糖，改善2型糖尿病小鼠的葡糖糖耐受能力。SPK1治疗3周后，Q-SPK1治疗组小鼠的体重明显减轻。Q-SPK1对2型糖尿病并发的多种脏器损伤如肝脏、胰腺等有较明显的保护作用。
另外，采用糖尿病大鼠皮肤损伤模型，研究SPK1对糖尿病性皮肤溃疡的治疗作用。实验结果显示，SPK1对糖尿病皮肤损伤具有明显的促愈合作用。
Sphingosine kinase1(SPK1) is a key enzyme in sphingolipid metabolism. Weanalyzed the amino acid sequences of SPK1and found that SPK1contained aconserved GK motif that is found in many acetylated proteins, suggesting that SPK1may be acetylated under certain conditions. We determined frstly whether SPK1might be acetylated in vivo. Flag-tagged SPK1(Flag-SPK1) was transfected intoHEK293cells and then cell lysates were immunoprecipitated with Flag M2beads.The immunoprecipitation (IP) products were subjected to Western blot analysis.Acetylated SPK1was detected. For in vitro acetylation assay, the IP products wereincubated with or without p300acetyltransferase in the presence of acetyl-CoA.Incubation with p300acetyltransferase resulted in an increased amount of acetylatedSPK1. Therefore, SPK1could be acetylated both in vivo and in vitro. Next wedetermined whether the two lysine residues in the GK motif of SPK1were acetylated.To do so, the two K in the GK motif of SPK1were mutated either to R or Q, whichwe termed as R-SPK1or Q-SPK1. SPK1acetylation was found only in W-SPK1, butnot in R-SPK1, suggesting that SPK1is acetylated at one or t wo lysines in itsconserved GK motif.
This post-translational protein modification of SPK1may be an importantregulation of protein function.Our result showed that acetylation increases SPK1stability. When the two K in the GK motif of SPK1were mutated to R or Q, theubiquitination of SPK1was blocked, which prevented its degradation. These resultsindicated that the processes of acetylation and ubiquitination that involve SPK1compete for the same sites on the two lysine residues in the SPK1GK motif and thatacetylation stabilizes the SPK1protein by block its ubiquitination. Then weinvestigated the effects of SPK1acetyaltion on cell function. The Q-SPK1stablyexpressed cells show a signifcantly larger size when compared with the parentalHEK293cells and with the W-SPK1and R-SPK1stably expressed cells. However,the growth rate of these cells was reduced dramatically. Flow cytometry revealed thatthe proportion of cells in S-phase was increased and the proportion of G2-/M-phasecells was reduced markedly in Q-SPK1stably expressed cells, in comparison to the other cells. Thisfnding indicated that SPK1acetyaltion plays important roles in cellgrowth, cell size and cell cycle progression.
Furthermore, we investigated the effects of SPK1in spontaneous KK/Ay type2diabetic mice model using an attenuated salmonella-mediated gene transger approach.It was demonstrated that Q-SPK1could markedly improve blood glucose level andglucose tolerance. Besides, Q-SPK1also lightened body weight and protected againsthepatic and pancreatic organ injury.
Also, we investigated the roles of SPK1in skin injury in streptozotocin(STZ)-induced diabetic rat model using plasmid pcDNA3-Flag-SPK1. The resultsshowed that SPK1promoted wound.
In conclusion, ourfndings indicated that acetylation regulates SPK1proteinstability, and controls cell growth and cell-cycle progression. And acetylated SPK1can improve blood glucose of type2diabetic mice. And SPK1could significantlyimprove diabetes caused skin damage.
SPK1蛋白的这种翻译后修饰可能是其蛋白功能的一种重要的调控方式。实验结果表明，SPK1乙酰化修饰后其稳定性增强；将GKGK结构域中的两个K突变为R或Q，封闭了SPK1的泛素化修饰，避免了被蛋白酶体降解。细胞形态上，稳定表达Q-SPK1的细胞与表达W-SPK1及R-SPK1的细胞相比体积变大，但细胞生长速度变慢；流式分析细胞周期发现，稳定表达Q-SPK1的细胞处于S期的细胞明显增多，G2期的则减少，表明Q-SPK1阻断细胞由S期向G2/M期的进程。综上，SPK1乙酰化在调控细胞生长、大小及细胞周期中有重要作用。
在体外实验基础上，以自发性2型糖尿病KK/Ay小鼠为动物模型，灌胃给予携带野生型及突变体spk1基因的减毒沙门氏菌，在动物整体水平评价SPK1乙酰化修饰对糖尿病动物血糖的调节作用。结果显示，口服携带Q-SPK1质粒的减毒沙门氏菌可以降低2型糖尿病小鼠KK/Ay的血糖，改善2型糖尿病小鼠的葡糖糖耐受能力。SPK1治疗3周后，Q-SPK1治疗组小鼠的体重明显减轻。Q-SPK1对2型糖尿病并发的多种脏器损伤如肝脏、胰腺等有较明显的保护作用。
另外，采用糖尿病大鼠皮肤损伤模型，研究SPK1对糖尿病性皮肤溃疡的治疗作用。实验结果显示，SPK1对糖尿病皮肤损伤具有明显的促愈合作用。
Sphingosine kinase1(SPK1) is a key enzyme in sphingolipid metabolism. Weanalyzed the amino acid sequences of SPK1and found that SPK1contained aconserved GK motif that is found in many acetylated proteins, suggesting that SPK1may be acetylated under certain conditions. We determined frstly whether SPK1might be acetylated in vivo. Flag-tagged SPK1(Flag-SPK1) was transfected intoHEK293cells and then cell lysates were immunoprecipitated with Flag M2beads.The immunoprecipitation (IP) products were subjected to Western blot analysis.Acetylated SPK1was detected. For in vitro acetylation assay, the IP products wereincubated with or without p300acetyltransferase in the presence of acetyl-CoA.Incubation with p300acetyltransferase resulted in an increased amount of acetylatedSPK1. Therefore, SPK1could be acetylated both in vivo and in vitro. Next wedetermined whether the two lysine residues in the GK motif of SPK1were acetylated.To do so, the two K in the GK motif of SPK1were mutated either to R or Q, whichwe termed as R-SPK1or Q-SPK1. SPK1acetylation was found only in W-SPK1, butnot in R-SPK1, suggesting that SPK1is acetylated at one or t wo lysines in itsconserved GK motif.
This post-translational protein modification of SPK1may be an importantregulation of protein function.Our result showed that acetylation increases SPK1stability. When the two K in the GK motif of SPK1were mutated to R or Q, theubiquitination of SPK1was blocked, which prevented its degradation. These resultsindicated that the processes of acetylation and ubiquitination that involve SPK1compete for the same sites on the two lysine residues in the SPK1GK motif and thatacetylation stabilizes the SPK1protein by block its ubiquitination. Then weinvestigated the effects of SPK1acetyaltion on cell function. The Q-SPK1stablyexpressed cells show a signifcantly larger size when compared with the parentalHEK293cells and with the W-SPK1and R-SPK1stably expressed cells. However,the growth rate of these cells was reduced dramatically. Flow cytometry revealed thatthe proportion of cells in S-phase was increased and the proportion of G2-/M-phasecells was reduced markedly in Q-SPK1stably expressed cells, in comparison to the other cells. Thisfnding indicated that SPK1acetyaltion plays important roles in cellgrowth, cell size and cell cycle progression.
Furthermore, we investigated the effects of SPK1in spontaneous KK/Ay type2diabetic mice model using an attenuated salmonella-mediated gene transger approach.It was demonstrated that Q-SPK1could markedly improve blood glucose level andglucose tolerance. Besides, Q-SPK1also lightened body weight and protected againsthepatic and pancreatic organ injury.
Also, we investigated the roles of SPK1in skin injury in streptozotocin(STZ)-induced diabetic rat model using plasmid pcDNA3-Flag-SPK1. The resultsshowed that SPK1promoted wound.
In conclusion, ourfndings indicated that acetylation regulates SPK1proteinstability, and controls cell growth and cell-cycle progression. And acetylated SPK1can improve blood glucose of type2diabetic mice. And SPK1could significantlyimprove diabetes caused skin damage.
引文
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