人肝癌细胞SMMC-7721过表达N-乙酰氨基葡萄糖转移酶V对整合蛋白β1的N-糖链结构、蛋白稳定性及其功能的影响
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摘要
细胞内糖蛋白的糖链在内质网和高尔基体中通过糖基转移酶和糖苷酶加工而形成。其中N-乙酰氨基葡萄糖转移酶(N-acetylglucosaminyltransferase，GnT)是一组催化N-糖链生成的加工酶类，主要催化N-糖链由高甘露糖型经杂合型向复杂型过渡并形成外围天线结构。根据加工产物的不同，可将N-乙酰氨基葡萄糖转移酶分为六种，分别为GnT-Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅵ。如果这些糖基转移酶缺失或过表达，就会造成具有重要功能的糖蛋白糖链改变，进而影响其功能。
糖蛋白糖链最常见的变化是N-糖链分子量大小和分支数变化。N-糖链分支数增加，往往归因于N-乙酰氨基葡萄糖转移酶Ⅴ(GnT-Ⅴ)的过表达。GnT-Ⅴ是分布在高尔基体中的合成糖蛋白N-糖链分支结构的关键酶，将GlcNAc基团转移至N-糖链核心α1，6臂的α-甘露糖上，催化形成N-糖链的GlcNAcβ1，6分支结构。GnT-Ⅴ加工众多糖蛋白，其中很多膜蛋白是细胞表面的粘附分子，GnT-Ⅴ过表达引起细胞表面粘附分子糖链改变，GlcNAcβ1，6分支增加。已有大量报道由GnT-Ⅴ引起的细胞表面粘附分子糖链GlcNAcβ1，6分支增加与肿瘤细胞侵袭和迁移密切相关。又有研究发现GnT-Ⅴ有一种与糖基转移酶酶活性无关的功能，就是可引起肿瘤血管生成，而血管生成是肿瘤发展及转移过程关键的一步。这些研究结果提示我们：GnT-Ⅴ参与细胞恶性转化、肿瘤转移的机制是多方面的。
我们前期实验用GnT-Ⅴ转染7721细胞，观察到一个值得注意的现象，就是细胞重要的粘附分子整合蛋白β1的蛋白表达与Mock(pcDNA3／7721)细胞相比显著增高。GnT-Ⅴ是糖链加工的酶，关于影响细胞表面粘附分子的蛋白含量方面鲜有报道。为了探讨肿瘤细胞中GnT-Ⅴ影响细胞恶性程度的分子机制，研究GnT-Ⅴ的糖基转移酶催化活性与细胞表面粘附分子表达改变的关系，根据文献，我们构建GnT-Ⅴ的C末端去除六个氨基酸序列cDNA的重组质粒pcDNA3-ΔcGnT-Ⅴ，ΔcGnT-Ⅴ含有几乎完整的蛋白结构区域而无酶活性，将其转染至7721细胞；将GnT-Ⅴ全长表达质粒(pcDNA3-wtGnT-Ⅴ)和空载体(pcDNA3)同时分别转入7721细胞，并对筛得三株稳转细胞进行鉴定，已确定外源性ΔcGnT-Ⅴ或GnT-Ⅴ的cDNA在7721细胞中表达，三株稳转细胞分别用Δc-7721(ΔcGnT-Ⅴ／7721)细胞，wt-7721(wtGnT-Ⅴ／7721)细胞，Mock(pcDNA3／7721)细胞表示。
首先检测了Mock，wt-7721，Δc-7721细胞中整合蛋白β1亚基的表达。与Mock细胞相比，wt-7721细胞中整合蛋白β1的表达比Mock细胞的高2.4倍左右(主要是成熟型β1增加)；Δc-7721中整合蛋白β1的表达比Mock细胞的明显降低。然后用实时荧光定量PCR方法及RT-PCR方法检测了Mock细胞，wt-7721细胞，Δc-7721细胞中整合蛋白β1亚基的mRNA水平，两种方法结果均显示整合蛋白β1亚基的mRNA水平无显著差别。进一步确认了GnT-Ⅴ过表达对整合蛋白β1亚基的调节机制是在转录后水平。应用同位素脉冲追踪实验(Pulse-chase)，分析了整合蛋白β1的稳定性。结果证明，wt-7721细胞中整合蛋白β1亚基降解变慢，半衰期16小时左右；而Δc-7721细胞中的整合蛋白β1亚基半衰期不到3小时；Mock细胞中的整合蛋白β1亚基半衰期10小时左右。凝集素IP实验结果表明：wt-7721细胞中整合蛋白β1的N-糖链呈多天线且GlcNAcβ1，6分支增加；Δc-7721细胞中整合蛋白β1的N-糖链呈高甘露糖型。wt-7721细胞中整合蛋白β1的N-糖链GlcNAcβ1，6分支增加与其蛋白的稳定性增加一致，说明整合蛋白β1的N-糖链GlcNAcβ1，6分支可延长其蛋白的半寿期：Δc-7721细胞由于ΔcGnT-Ⅴ的转入使内源性GnT-Ⅴ的酶活性降低，导致整合蛋白β1的N-糖链不能进一步加工成熟，其携带的N-糖链停留在高甘露糖型的不成熟状态，然后被蛋白酶体降解。上述实验结果表明GnT-Ⅴ对整合蛋白β1的上调是由于N-糖链GlcNAcβ1，6分支加强其蛋白的稳定性，与GnT-Ⅴ的催化活性密切相关。Δc-7721由于缺少GnT-Ⅴ活性，导致其整合蛋白β1的稳定性下降。
为了阐明糖基转移酶的过表达使细胞膜上粘附分子蛋白糖链结构类型的改变是否能够调节信号转导强度，从而影响细胞的生物学行为，本文进一步研究了N-糖链分支数改变的整合蛋白β1对其介导的信号分子表达及磷酸化水平变化及其对肝癌细胞侵袭、迁移及抗凋亡能力的影响。结果发现，wt-7721中GnT-Ⅴ的过表达导致细胞迁移与侵袭能力增强是由于整合蛋白β1介导细胞—ECM相互作用，FAK蛋白激酶活性被持续激活；PTEN的蛋白水平降低也能刺激PI3-K／Akt途径，增加抗凋亡能力。过表达无催化活性的ΔcGnT8-Ⅴ的Δc-7721细胞PTEN的蛋白水
平明显上调，而FAK蛋白激酶活性、PI3-K／Akt途径被抑制，细胞侵袭与迁移能力下降很多，这可能为今后的分子干预治疗寻找新的靶分子提供研究基础。
Malignant behaviors in transformed cells and human tumors such as migration and invasion are highly associated with the significant increase of asparagine-linked glycans (N-glycans) containing GlcNAcβ1,6 branching. The β1-6 branching of carbohydrates is the result of β1-6 N-acetylglucosaminyltransferase V , a trans Golgi enzyme encoded by the Mgat5 (mannoside acetylglucosaminyltransferase 5) gene, which adds N-acetylglucosamine (GlcNAc) to the mannose of the trimannosyl core in a β1-6 linkage. Results from recent studies showed the expression of β1,6-GlcNAc branched N-linked oligosaccharides in human mammary, colon, hepatic, and glial tumors and confirm the notion that the GlcNAcβ1,6 branched structure acquires the properties of cancer invasion and metastasis. Therefore, GnT-V was taken as one of the most important glycosyltransferases in tumor growth and metastasis . Integrins are composed of a and β subunits, which are all major carriers of N-glycans .Changes in N-glycans of these integrins have the key effects on cell-cell and cell-extracellular matrix (ECM) interactions.
Reportedly, the minimal catalytic domain of GnT-V was existed in its carboxyl -terminus, and deletion of as few as 4-8 amino acids from its carboxyl-terminus destroys its catalytic activity .In this study, an enzymatic inactive mutant of GnT-V (AcGnT-V) was constructed. Positive (pcDNA-wtGnT-V or pcDNA3-AcGnT-V) and negative (empty vector) clones were selected, and transfectants with higher expression levels of wt- or Ac- GnT-V were used for the experiments described herein. The transfectants from pcDNA3, pcDNA3-wtGnT-V and pcDNA3-AcGnT-V were designated as Mock, wt-7721 and Ac-7721 cells, respectively. We investigated the integrin β1 expression pattern in the Mock, wt-7721 and Ac-7721 cells. Our results showed that integrin β1 was increased in wt-7721 cells compared with Mock cells, while decreased in Ac-7721 cells .Integrin β1 in AcGnT-V transfectants (Ac-7721) showed attenuation of the number of GlcNAcβ1,6 branching, whereas those in
wtGnT-V transfectants (wt-7721) presented a GlcNAcβ1,6-rich pattern. High integrin β1 expression was observed in wt-7721 compared with Mock cells ( 7721 cell transfected with the vector pcDNA3), while transfection of AcGnT-V decreased the integrin β1, despite of no significant changes on integrin β1 mRNA level in these cell lines. Pulse-chase experiment showed that Integrin β1 in Ac-7721 was prone to quick degradation and its half-life was less than 3 h, on the contrary, the alleviating degradation of β1 subunit was observed in wt-7721 where the β1 subunit half-life was about 16 h, meanwhile, the degradation rate of β1 subunit in Mock cells was in between, about 10h.
More effective in promoting cell migration toward fibronectin and invasion through Matrigel was observed in wt-7721 while this was almost suppressed in Ac-7721. In wt-7721 cells, the total level of PKB and FAK did not change, but the levels of p-PKB Ser473,p-GSK3-β Ser9 and p-FAK were significantly increased; On the contrary,in Ac-7721 cells, the levels of p-PKB Ser473, p-GSK3-p- Ser9 and p-FAK levels were markedly decreased.Our results suggest that the addition of GlcNAcβ1,6 branching caused more fully glycosylated mature form on integrin piand inhibited β1 protein degradation; on the other hand,changes in N-linked glycosylation caused by A cGnT-V directed degradation of β1 integrin and subsequently inhibited cell migration and invasion. Glycosylation caused by GnT-V directs integrin β1 stability and more delivery to plasma membrane, subsequently promotes FN-based cell migration and invasion. Thus, our findings support the notion that GnT-V up-regulates β1 integrin preferably through enhancing its half-life in the enzymatic activity-dependent manner.
糖蛋白糖链最常见的变化是N-糖链分子量大小和分支数变化。N-糖链分支数增加，往往归因于N-乙酰氨基葡萄糖转移酶Ⅴ(GnT-Ⅴ)的过表达。GnT-Ⅴ是分布在高尔基体中的合成糖蛋白N-糖链分支结构的关键酶，将GlcNAc基团转移至N-糖链核心α1，6臂的α-甘露糖上，催化形成N-糖链的GlcNAcβ1，6分支结构。GnT-Ⅴ加工众多糖蛋白，其中很多膜蛋白是细胞表面的粘附分子，GnT-Ⅴ过表达引起细胞表面粘附分子糖链改变，GlcNAcβ1，6分支增加。已有大量报道由GnT-Ⅴ引起的细胞表面粘附分子糖链GlcNAcβ1，6分支增加与肿瘤细胞侵袭和迁移密切相关。又有研究发现GnT-Ⅴ有一种与糖基转移酶酶活性无关的功能，就是可引起肿瘤血管生成，而血管生成是肿瘤发展及转移过程关键的一步。这些研究结果提示我们：GnT-Ⅴ参与细胞恶性转化、肿瘤转移的机制是多方面的。
我们前期实验用GnT-Ⅴ转染7721细胞，观察到一个值得注意的现象，就是细胞重要的粘附分子整合蛋白β1的蛋白表达与Mock(pcDNA3／7721)细胞相比显著增高。GnT-Ⅴ是糖链加工的酶，关于影响细胞表面粘附分子的蛋白含量方面鲜有报道。为了探讨肿瘤细胞中GnT-Ⅴ影响细胞恶性程度的分子机制，研究GnT-Ⅴ的糖基转移酶催化活性与细胞表面粘附分子表达改变的关系，根据文献，我们构建GnT-Ⅴ的C末端去除六个氨基酸序列cDNA的重组质粒pcDNA3-ΔcGnT-Ⅴ，ΔcGnT-Ⅴ含有几乎完整的蛋白结构区域而无酶活性，将其转染至7721细胞；将GnT-Ⅴ全长表达质粒(pcDNA3-wtGnT-Ⅴ)和空载体(pcDNA3)同时分别转入7721细胞，并对筛得三株稳转细胞进行鉴定，已确定外源性ΔcGnT-Ⅴ或GnT-Ⅴ的cDNA在7721细胞中表达，三株稳转细胞分别用Δc-7721(ΔcGnT-Ⅴ／7721)细胞，wt-7721(wtGnT-Ⅴ／7721)细胞，Mock(pcDNA3／7721)细胞表示。
首先检测了Mock，wt-7721，Δc-7721细胞中整合蛋白β1亚基的表达。与Mock细胞相比，wt-7721细胞中整合蛋白β1的表达比Mock细胞的高2.4倍左右(主要是成熟型β1增加)；Δc-7721中整合蛋白β1的表达比Mock细胞的明显降低。然后用实时荧光定量PCR方法及RT-PCR方法检测了Mock细胞，wt-7721细胞，Δc-7721细胞中整合蛋白β1亚基的mRNA水平，两种方法结果均显示整合蛋白β1亚基的mRNA水平无显著差别。进一步确认了GnT-Ⅴ过表达对整合蛋白β1亚基的调节机制是在转录后水平。应用同位素脉冲追踪实验(Pulse-chase)，分析了整合蛋白β1的稳定性。结果证明，wt-7721细胞中整合蛋白β1亚基降解变慢，半衰期16小时左右；而Δc-7721细胞中的整合蛋白β1亚基半衰期不到3小时；Mock细胞中的整合蛋白β1亚基半衰期10小时左右。凝集素IP实验结果表明：wt-7721细胞中整合蛋白β1的N-糖链呈多天线且GlcNAcβ1，6分支增加；Δc-7721细胞中整合蛋白β1的N-糖链呈高甘露糖型。wt-7721细胞中整合蛋白β1的N-糖链GlcNAcβ1，6分支增加与其蛋白的稳定性增加一致，说明整合蛋白β1的N-糖链GlcNAcβ1，6分支可延长其蛋白的半寿期：Δc-7721细胞由于ΔcGnT-Ⅴ的转入使内源性GnT-Ⅴ的酶活性降低，导致整合蛋白β1的N-糖链不能进一步加工成熟，其携带的N-糖链停留在高甘露糖型的不成熟状态，然后被蛋白酶体降解。上述实验结果表明GnT-Ⅴ对整合蛋白β1的上调是由于N-糖链GlcNAcβ1，6分支加强其蛋白的稳定性，与GnT-Ⅴ的催化活性密切相关。Δc-7721由于缺少GnT-Ⅴ活性，导致其整合蛋白β1的稳定性下降。
为了阐明糖基转移酶的过表达使细胞膜上粘附分子蛋白糖链结构类型的改变是否能够调节信号转导强度，从而影响细胞的生物学行为，本文进一步研究了N-糖链分支数改变的整合蛋白β1对其介导的信号分子表达及磷酸化水平变化及其对肝癌细胞侵袭、迁移及抗凋亡能力的影响。结果发现，wt-7721中GnT-Ⅴ的过表达导致细胞迁移与侵袭能力增强是由于整合蛋白β1介导细胞—ECM相互作用，FAK蛋白激酶活性被持续激活；PTEN的蛋白水平降低也能刺激PI3-K／Akt途径，增加抗凋亡能力。过表达无催化活性的ΔcGnT8-Ⅴ的Δc-7721细胞PTEN的蛋白水
平明显上调，而FAK蛋白激酶活性、PI3-K／Akt途径被抑制，细胞侵袭与迁移能力下降很多，这可能为今后的分子干预治疗寻找新的靶分子提供研究基础。
Malignant behaviors in transformed cells and human tumors such as migration and invasion are highly associated with the significant increase of asparagine-linked glycans (N-glycans) containing GlcNAcβ1,6 branching. The β1-6 branching of carbohydrates is the result of β1-6 N-acetylglucosaminyltransferase V , a trans Golgi enzyme encoded by the Mgat5 (mannoside acetylglucosaminyltransferase 5) gene, which adds N-acetylglucosamine (GlcNAc) to the mannose of the trimannosyl core in a β1-6 linkage. Results from recent studies showed the expression of β1,6-GlcNAc branched N-linked oligosaccharides in human mammary, colon, hepatic, and glial tumors and confirm the notion that the GlcNAcβ1,6 branched structure acquires the properties of cancer invasion and metastasis. Therefore, GnT-V was taken as one of the most important glycosyltransferases in tumor growth and metastasis . Integrins are composed of a and β subunits, which are all major carriers of N-glycans .Changes in N-glycans of these integrins have the key effects on cell-cell and cell-extracellular matrix (ECM) interactions.
Reportedly, the minimal catalytic domain of GnT-V was existed in its carboxyl -terminus, and deletion of as few as 4-8 amino acids from its carboxyl-terminus destroys its catalytic activity .In this study, an enzymatic inactive mutant of GnT-V (AcGnT-V) was constructed. Positive (pcDNA-wtGnT-V or pcDNA3-AcGnT-V) and negative (empty vector) clones were selected, and transfectants with higher expression levels of wt- or Ac- GnT-V were used for the experiments described herein. The transfectants from pcDNA3, pcDNA3-wtGnT-V and pcDNA3-AcGnT-V were designated as Mock, wt-7721 and Ac-7721 cells, respectively. We investigated the integrin β1 expression pattern in the Mock, wt-7721 and Ac-7721 cells. Our results showed that integrin β1 was increased in wt-7721 cells compared with Mock cells, while decreased in Ac-7721 cells .Integrin β1 in AcGnT-V transfectants (Ac-7721) showed attenuation of the number of GlcNAcβ1,6 branching, whereas those in
wtGnT-V transfectants (wt-7721) presented a GlcNAcβ1,6-rich pattern. High integrin β1 expression was observed in wt-7721 compared with Mock cells ( 7721 cell transfected with the vector pcDNA3), while transfection of AcGnT-V decreased the integrin β1, despite of no significant changes on integrin β1 mRNA level in these cell lines. Pulse-chase experiment showed that Integrin β1 in Ac-7721 was prone to quick degradation and its half-life was less than 3 h, on the contrary, the alleviating degradation of β1 subunit was observed in wt-7721 where the β1 subunit half-life was about 16 h, meanwhile, the degradation rate of β1 subunit in Mock cells was in between, about 10h.
More effective in promoting cell migration toward fibronectin and invasion through Matrigel was observed in wt-7721 while this was almost suppressed in Ac-7721. In wt-7721 cells, the total level of PKB and FAK did not change, but the levels of p-PKB Ser473,p-GSK3-β Ser9 and p-FAK were significantly increased; On the contrary,in Ac-7721 cells, the levels of p-PKB Ser473, p-GSK3-p- Ser9 and p-FAK levels were markedly decreased.Our results suggest that the addition of GlcNAcβ1,6 branching caused more fully glycosylated mature form on integrin piand inhibited β1 protein degradation; on the other hand,changes in N-linked glycosylation caused by A cGnT-V directed degradation of β1 integrin and subsequently inhibited cell migration and invasion. Glycosylation caused by GnT-V directs integrin β1 stability and more delivery to plasma membrane, subsequently promotes FN-based cell migration and invasion. Thus, our findings support the notion that GnT-V up-regulates β1 integrin preferably through enhancing its half-life in the enzymatic activity-dependent manner.
引文
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