高表达β2糖蛋白Ⅰ在乙型肝炎病毒入侵肝细胞初始环节中的作用研究
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摘要
乙型肝炎病毒(HBV)感染是全球主要的公共健康问题，超过20亿人感染HBV，有3.5-4亿人为慢性感染，每年50-100万人死于乙肝相关性终末期肝病。我国属于HBV高流行区，HBsAg检出率为10%，有9,300万慢性HBV感染者，每年约35万人死于乙肝相关性肝硬化和肝细胞癌。目前针对HBV感染的防治，主要依赖于婴儿期乙肝疫苗的预防接种和感染者抑制病毒复制。然而，阻止HBV入侵肝细胞和诱导肝细胞增殖则是更有效的治疗方案。迄今为止，HBV入侵肝细胞的分子机制仍不能明确。
目前，普遍认为HBV入侵肝细胞是由病毒包膜蛋白HBsAg调节的。HBsAg蛋白包括大、中、小三种形式，其中，表面抗原大蛋白(LHBs)由前S1、前S2和S区编码蛋白组成，中蛋白(MHBs)由前S2和S区编码蛋白组成，小蛋白(SHBs)由S区编码蛋白组成。大蛋白前S1区被认为是HBV入侵肝细胞的关键部位，可以与HBV受体结合。近年来，已发现很多HBV结合伴侣，可能是HBV入侵肝细胞途径中的相关蛋白或者在肝细胞膜上的受体，主要有：β2糖蛋白I(beta2-GPI)、膜联蛋白V、膜联蛋白II (annexin II, ANX2)、去唾液酸糖蛋白受体(ASGPR)、纤维连接蛋白(Fibronectin)、糖胺聚糖(GAG)、鳞状细胞癌抗原(SCCA)、羟肽酶D等等。最近研究认为，钠离子牛磺胆酸共转运多肽(NTCP)是人类乙型和丁型肝炎病毒的功能性受体。HBV的宿主特异性和嗜肝性与肝细胞表面特异性受体有关，深入探索HBV究竟通过哪种途径如何入侵肝细胞至关重要。
β2糖蛋白I是血浆中含量丰富的糖蛋白之一，主要由肝细胞合成，与HBsAg具有高亲和结合的特性。近年来，关于beta2-GPI的研究主要集中于作为自身抗原或共因子，参与抗磷脂综合征等自身免疫性疾病血栓事件的发生。但有趣的是，beta2-GPI是个易变的分子，它的构象和功能随着与其结合的分子或者复合物的变化而改变。Beta2-GPI有五个功能区组成，类似于补体调控蛋白，第五功能区结构特殊，带有高度正电荷区。电子显微镜观察显示，健康人血浆中beta2-GPI以非致病的环状形式存在，即第一功能区和第五功能区结合。当阴离子结构与第五功能区结合，beta2-GPI由闭合的环状开放呈“S”型，以利于与其他分子结合，表现多样的生物学活性。已有研究发现，HBsAg与beta2-GPI第五功能区结合，beta2-GPI的糖基不能改变其与HBsAg的亲和能力，在HBV病毒复制活跃期，HBsAg与beta2-GPI结合能力增强，还鉴定出beta2-GPI与肝癌细胞SMMC-7721细胞膜上annexin II特异性结合。我们推测：以beta2-GPI为中介，通过HBV-beta2-GPI-ANX2路径入侵肝细胞，成为乙肝病毒亲嗜肝细胞的可能途径之一。
本研究首先以L02、SMMC-7721、HepG2、HepG2.2.15、293T、CHO细胞为研究对象，采用western blot方法检测不同细胞中beta2-GPI的表达，其中：肝癌细胞SMMC-7721用于前期实验；HepG2.2.15由HepG2衍生而来，为HBVDNA转染HepG2的稳转细胞系，能持续、稳定表达HBV成熟病毒颗粒和HBsAg、HBeAg；L02为永化化胎儿正常肝脏细胞，作为正常对照；人胚肾细胞HEK-293T和中国仓鼠卵巢癌细胞CHO-K1具有较高转染效率，293T细胞还多用于病毒包装的研究。结果表明，HepG2.2.15细胞中beta2-GPI表达明显高于L02、SMMC-7721和HepG2细胞，而293T和CHO细胞中表达很少。通过qRT-PCR方法检测同源细胞系HepG2和HepG2.2.15中beta2-GPI mRNA水平，发现HepG2.2.15细胞中beta2-GPI mRNA水平也明显升高。接下来，选取L02、HepG2、HepG2.2.15和293T细胞为研究对象，将不同浓度梯度HBsAg或（和）beta2-GPI蛋白(0-800ng mL-1)与细胞共孵育，ELISA检测发现beta2-GPI能增强HBsAg与不同细胞表面的结合，尤其是与L02和293T细胞，但无beta2-GPI浓度依赖性。已知beta2-GPI能与细胞膜上annexin II结合，我们认为HBsAg与不同细胞表面结合能力的差异也可能与annexin II有关。进一步通过westernblot法检测不同细胞中annexin II的表达，发现HepG2.2.15细胞中annexin II含量明显低于L02、SMMC-7721、HepG2和293T细胞，CHO细胞中有少量表达。
进一步研究HBV和HBsAg与beta2-GPI的相互作用，将HBV和HBsAg表达载体分别与beta2-GPI质粒共转染293T细胞，发现HBV和LHBsAg直接增强beta2-GPI表达，MHBsAg和SHBsAg对beta2-GPI表达无影响，还发现beta2-GPI能抑制HBsAg分泌。此外，将HBV表达载体转染HepG2细胞中，HBV能降低annexin II表达。采用细胞免疫标记技术，通过共聚焦显微镜观察发现，HepG2.2.15细胞中beta2-GPI分别与HBsAg和annexin II共定位于细胞质，annexin II与HBsAg也共定位于细胞质；HepG2细胞中，beta2-GPI和NTCP共定位于细胞膜，beta2-GPI和annexin II共定位于细胞质中。
综上研究，HBV使beta2-GPI表达上调，高表达beta2-GPI促进HBsAg与细胞表面结合，有利于病毒与NTCP受体结合，beta2-GPI与annexin II结合可能促进病毒与细胞表面结合和膜融合的发生。此结论为深入探索HBV入侵肝细胞的分子机制开辟了新思路和新方向。
Human hepatitis B virus (HBV) infection is a global public health problem.Approximately2billion people are infected with HBV, and among them3.5-4million are chronic HBV carriers. Hepatitis B causes about6.5million deaths ofHBV-related cirrhosis and hepatocellular carcinoma annually. In China, HBV infection is ahighly endemic. The seroepideminological survey on HBV infection showed that HBsAgcarrier rate was10%in the overall population. Accordingly, there were an estimated93million HBV carriers, and35million die of cirrhosis and hepatocellular carcinoma each year.Current therapies include immune protection and sustained suppression of viral replication.However, inhibition of virus entry and the induction of hepatocyte proliferation are attractivetherapeutic strategies. Up to now, the early stages of HBV infection (i.e., attachment,receptor binding, and fusion) are not completely understood.
Cellular entry of HBV is mediated by viral envelope proteins that aredesignated large (LHBs), middle (MHBs), and small (SHBs). The LHBsencompasses the PreS1domain, the PreS2domain and the S domain; the MHBsencompasses the PreS2and S domain and the SHBs consists of the S domain. Thepre-S1domain of the LHBs envelope protein is a primary determinant of binding toone or more receptors. Several proteins have been reported as viral receptors thatinteract with HBV surface proteins, including beta2-glycoprotein I (beta2-GPI),annexin V, annexin II (ANX2), asialoglycoprotein receptor (ASGPR), fibronectin,glycosaminoglycan (GAG), squamous cell carcinoma antige (SCCA),carboxypeptidase D and others; but no protein has been confirmed to support viralentry. Recently, it has been proposed that sodium taurocholate co-transportingpolypeptide (NTCP) is a functional receptor for human HBV and hepatitis D virusentry. Although the hepatotropism of HBV and its host specificity are believed to be associated with specific receptor binding, it remains unclear which pathway orpathways are essential for HBV entry.
It has been shown that beta2-GPI, a human plasmatic protein primarilysynthesized in the liver, can bind to recombinant hepatitis B surface antigen(rHBsAg). However, beta2-GPI is known to act as a major autoantigen inantiphospholipid syndrome (APS), an autoantibody-mediated thrombotic disorder.Interestingly, beta2-GPI is a flexible molecule, and its conformation and functionalactivity depend on interactions with its surroundings. It consists of5homologousdomains (domains I-V), all of which are complement control protein repeats. Inplasma, beta2-GPI remains in the nonpathogenic circular form, with domains V and Iconnected. The protein opens into an S-shaped configuration when interacting withanionic surfaces via domain V. It was observed that glycosylation of beta2-GPI didnot change its high-affinity binding to rHBsAg, and rHBsAg and anionicphospholipids shared the same binding region in the fifth domain of beta2-GPI.Furthermore, the binding activity of beta2-GPI to HBsAg was higher in the serum ofpatients in the active virus replication phase. In addition, annexin II was reported tobe a possible receptor for beta2-GPI on the membrane of SMMC-7721hepatomacells, assisting in bridging HBV entry. Altogether, it can be concluded that beta2-GPImight be crucial for the initial stages of HBV infection.
In this study, several cell lines were used to clarify the purpose of ourexperiment. Human hepatoma SMMC-7721cell line was used in our previous study.HepG2.2.15is a HBV-producing cell line, derived from human hepatoma cell lineHepG2. L02is an immortal human hepatic cell line. Human embryonickidney cell line, HEK-293T, has high transfection efficiency. Chinese HamsterOvary (CHO) cells represent a hugely popular research tool in the molecular biologycommunity. L02,293T and CHO cells were used as control in our study. Firstly,western blot and qRT-PCR analyses revealed that beta2-GPI expression wasupregulated in HepG2.2.15cells at both the mRNA and the protein level and wasalmost non-existent in293T and CHO cells. When rHBsAg (200ng mL-1) was pre-incubated with beta2-GPI (0-800ng mL-1) before contact with cells, ELISAanalyses demonstrated that beta2-GPI enhanced the ability of HBsAg to bind to cellsurfaces, and there was differential adhesion to L02, HepG2, HepG2.2.15, and293Tcells. However, there was no dose-dependent response for beta2-GPI. Thedifferences in the binding abilities of these cells might be attributable to differentexpression levels of annexin II. Then, western blot was performed to detect theexpression of annexin II in L02, SMMC-7721, HepG2, HepG2.2.15,293T and CHOcells. The result showed that annexin II was expressed at lower levels in HepG2.2.15cells compared to L02, HepG2, and SMMC-7721cells.
Additionally, western blot and ELISA were then performed to assess the effectsof HBV and the HBsAg domain on beta2-GPI expression in co-transfected293Tcells, and determine the effects of HBV on annexin II expression in transfectedHepG2cells. This study revealed that HBV and the large HBV envelope proteinincreased beta2-GPI expression, and the middle and the small surface protein had noeffect on beta2-GPI expression. And beta2-GPI can inhibit the secretion of HBsAg inHBV life cycle. In addition, HBV can decrease annexin II expression in transfectedHepG2cells. Further investigation indicated that beta2-GPI colocalized with HBsAgin the cytosol of HepG2.2.15cells, with sodium taurocholate co-transportingpolypeptide (NTCP) on the cell membrane in NTCP-complemented HepG2cells,and with annexin II in the cytosol of HepG2and HepG2.2.15cells. And annexin IIcolocalized with HBsAg in the cytosol of HepG2.2.15cells.
In conclusion, our findings demonstrated that high expression of beta2-GPIenhances HBsAg binding to cell surfaces, thus contributing to virus particle transfer to theNTCP receptor and interaction with annexin II for viral binding and membrane fusion. Theyprovide new insights into the route of human HBV entry into hepatocytes.
目前，普遍认为HBV入侵肝细胞是由病毒包膜蛋白HBsAg调节的。HBsAg蛋白包括大、中、小三种形式，其中，表面抗原大蛋白(LHBs)由前S1、前S2和S区编码蛋白组成，中蛋白(MHBs)由前S2和S区编码蛋白组成，小蛋白(SHBs)由S区编码蛋白组成。大蛋白前S1区被认为是HBV入侵肝细胞的关键部位，可以与HBV受体结合。近年来，已发现很多HBV结合伴侣，可能是HBV入侵肝细胞途径中的相关蛋白或者在肝细胞膜上的受体，主要有：β2糖蛋白I(beta2-GPI)、膜联蛋白V、膜联蛋白II (annexin II, ANX2)、去唾液酸糖蛋白受体(ASGPR)、纤维连接蛋白(Fibronectin)、糖胺聚糖(GAG)、鳞状细胞癌抗原(SCCA)、羟肽酶D等等。最近研究认为，钠离子牛磺胆酸共转运多肽(NTCP)是人类乙型和丁型肝炎病毒的功能性受体。HBV的宿主特异性和嗜肝性与肝细胞表面特异性受体有关，深入探索HBV究竟通过哪种途径如何入侵肝细胞至关重要。
β2糖蛋白I是血浆中含量丰富的糖蛋白之一，主要由肝细胞合成，与HBsAg具有高亲和结合的特性。近年来，关于beta2-GPI的研究主要集中于作为自身抗原或共因子，参与抗磷脂综合征等自身免疫性疾病血栓事件的发生。但有趣的是，beta2-GPI是个易变的分子，它的构象和功能随着与其结合的分子或者复合物的变化而改变。Beta2-GPI有五个功能区组成，类似于补体调控蛋白，第五功能区结构特殊，带有高度正电荷区。电子显微镜观察显示，健康人血浆中beta2-GPI以非致病的环状形式存在，即第一功能区和第五功能区结合。当阴离子结构与第五功能区结合，beta2-GPI由闭合的环状开放呈“S”型，以利于与其他分子结合，表现多样的生物学活性。已有研究发现，HBsAg与beta2-GPI第五功能区结合，beta2-GPI的糖基不能改变其与HBsAg的亲和能力，在HBV病毒复制活跃期，HBsAg与beta2-GPI结合能力增强，还鉴定出beta2-GPI与肝癌细胞SMMC-7721细胞膜上annexin II特异性结合。我们推测：以beta2-GPI为中介，通过HBV-beta2-GPI-ANX2路径入侵肝细胞，成为乙肝病毒亲嗜肝细胞的可能途径之一。
本研究首先以L02、SMMC-7721、HepG2、HepG2.2.15、293T、CHO细胞为研究对象，采用western blot方法检测不同细胞中beta2-GPI的表达，其中：肝癌细胞SMMC-7721用于前期实验；HepG2.2.15由HepG2衍生而来，为HBVDNA转染HepG2的稳转细胞系，能持续、稳定表达HBV成熟病毒颗粒和HBsAg、HBeAg；L02为永化化胎儿正常肝脏细胞，作为正常对照；人胚肾细胞HEK-293T和中国仓鼠卵巢癌细胞CHO-K1具有较高转染效率，293T细胞还多用于病毒包装的研究。结果表明，HepG2.2.15细胞中beta2-GPI表达明显高于L02、SMMC-7721和HepG2细胞，而293T和CHO细胞中表达很少。通过qRT-PCR方法检测同源细胞系HepG2和HepG2.2.15中beta2-GPI mRNA水平，发现HepG2.2.15细胞中beta2-GPI mRNA水平也明显升高。接下来，选取L02、HepG2、HepG2.2.15和293T细胞为研究对象，将不同浓度梯度HBsAg或（和）beta2-GPI蛋白(0-800ng mL-1)与细胞共孵育，ELISA检测发现beta2-GPI能增强HBsAg与不同细胞表面的结合，尤其是与L02和293T细胞，但无beta2-GPI浓度依赖性。已知beta2-GPI能与细胞膜上annexin II结合，我们认为HBsAg与不同细胞表面结合能力的差异也可能与annexin II有关。进一步通过westernblot法检测不同细胞中annexin II的表达，发现HepG2.2.15细胞中annexin II含量明显低于L02、SMMC-7721、HepG2和293T细胞，CHO细胞中有少量表达。
进一步研究HBV和HBsAg与beta2-GPI的相互作用，将HBV和HBsAg表达载体分别与beta2-GPI质粒共转染293T细胞，发现HBV和LHBsAg直接增强beta2-GPI表达，MHBsAg和SHBsAg对beta2-GPI表达无影响，还发现beta2-GPI能抑制HBsAg分泌。此外，将HBV表达载体转染HepG2细胞中，HBV能降低annexin II表达。采用细胞免疫标记技术，通过共聚焦显微镜观察发现，HepG2.2.15细胞中beta2-GPI分别与HBsAg和annexin II共定位于细胞质，annexin II与HBsAg也共定位于细胞质；HepG2细胞中，beta2-GPI和NTCP共定位于细胞膜，beta2-GPI和annexin II共定位于细胞质中。
综上研究，HBV使beta2-GPI表达上调，高表达beta2-GPI促进HBsAg与细胞表面结合，有利于病毒与NTCP受体结合，beta2-GPI与annexin II结合可能促进病毒与细胞表面结合和膜融合的发生。此结论为深入探索HBV入侵肝细胞的分子机制开辟了新思路和新方向。
Human hepatitis B virus (HBV) infection is a global public health problem.Approximately2billion people are infected with HBV, and among them3.5-4million are chronic HBV carriers. Hepatitis B causes about6.5million deaths ofHBV-related cirrhosis and hepatocellular carcinoma annually. In China, HBV infection is ahighly endemic. The seroepideminological survey on HBV infection showed that HBsAgcarrier rate was10%in the overall population. Accordingly, there were an estimated93million HBV carriers, and35million die of cirrhosis and hepatocellular carcinoma each year.Current therapies include immune protection and sustained suppression of viral replication.However, inhibition of virus entry and the induction of hepatocyte proliferation are attractivetherapeutic strategies. Up to now, the early stages of HBV infection (i.e., attachment,receptor binding, and fusion) are not completely understood.
Cellular entry of HBV is mediated by viral envelope proteins that aredesignated large (LHBs), middle (MHBs), and small (SHBs). The LHBsencompasses the PreS1domain, the PreS2domain and the S domain; the MHBsencompasses the PreS2and S domain and the SHBs consists of the S domain. Thepre-S1domain of the LHBs envelope protein is a primary determinant of binding toone or more receptors. Several proteins have been reported as viral receptors thatinteract with HBV surface proteins, including beta2-glycoprotein I (beta2-GPI),annexin V, annexin II (ANX2), asialoglycoprotein receptor (ASGPR), fibronectin,glycosaminoglycan (GAG), squamous cell carcinoma antige (SCCA),carboxypeptidase D and others; but no protein has been confirmed to support viralentry. Recently, it has been proposed that sodium taurocholate co-transportingpolypeptide (NTCP) is a functional receptor for human HBV and hepatitis D virusentry. Although the hepatotropism of HBV and its host specificity are believed to be associated with specific receptor binding, it remains unclear which pathway orpathways are essential for HBV entry.
It has been shown that beta2-GPI, a human plasmatic protein primarilysynthesized in the liver, can bind to recombinant hepatitis B surface antigen(rHBsAg). However, beta2-GPI is known to act as a major autoantigen inantiphospholipid syndrome (APS), an autoantibody-mediated thrombotic disorder.Interestingly, beta2-GPI is a flexible molecule, and its conformation and functionalactivity depend on interactions with its surroundings. It consists of5homologousdomains (domains I-V), all of which are complement control protein repeats. Inplasma, beta2-GPI remains in the nonpathogenic circular form, with domains V and Iconnected. The protein opens into an S-shaped configuration when interacting withanionic surfaces via domain V. It was observed that glycosylation of beta2-GPI didnot change its high-affinity binding to rHBsAg, and rHBsAg and anionicphospholipids shared the same binding region in the fifth domain of beta2-GPI.Furthermore, the binding activity of beta2-GPI to HBsAg was higher in the serum ofpatients in the active virus replication phase. In addition, annexin II was reported tobe a possible receptor for beta2-GPI on the membrane of SMMC-7721hepatomacells, assisting in bridging HBV entry. Altogether, it can be concluded that beta2-GPImight be crucial for the initial stages of HBV infection.
In this study, several cell lines were used to clarify the purpose of ourexperiment. Human hepatoma SMMC-7721cell line was used in our previous study.HepG2.2.15is a HBV-producing cell line, derived from human hepatoma cell lineHepG2. L02is an immortal human hepatic cell line. Human embryonickidney cell line, HEK-293T, has high transfection efficiency. Chinese HamsterOvary (CHO) cells represent a hugely popular research tool in the molecular biologycommunity. L02,293T and CHO cells were used as control in our study. Firstly,western blot and qRT-PCR analyses revealed that beta2-GPI expression wasupregulated in HepG2.2.15cells at both the mRNA and the protein level and wasalmost non-existent in293T and CHO cells. When rHBsAg (200ng mL-1) was pre-incubated with beta2-GPI (0-800ng mL-1) before contact with cells, ELISAanalyses demonstrated that beta2-GPI enhanced the ability of HBsAg to bind to cellsurfaces, and there was differential adhesion to L02, HepG2, HepG2.2.15, and293Tcells. However, there was no dose-dependent response for beta2-GPI. Thedifferences in the binding abilities of these cells might be attributable to differentexpression levels of annexin II. Then, western blot was performed to detect theexpression of annexin II in L02, SMMC-7721, HepG2, HepG2.2.15,293T and CHOcells. The result showed that annexin II was expressed at lower levels in HepG2.2.15cells compared to L02, HepG2, and SMMC-7721cells.
Additionally, western blot and ELISA were then performed to assess the effectsof HBV and the HBsAg domain on beta2-GPI expression in co-transfected293Tcells, and determine the effects of HBV on annexin II expression in transfectedHepG2cells. This study revealed that HBV and the large HBV envelope proteinincreased beta2-GPI expression, and the middle and the small surface protein had noeffect on beta2-GPI expression. And beta2-GPI can inhibit the secretion of HBsAg inHBV life cycle. In addition, HBV can decrease annexin II expression in transfectedHepG2cells. Further investigation indicated that beta2-GPI colocalized with HBsAgin the cytosol of HepG2.2.15cells, with sodium taurocholate co-transportingpolypeptide (NTCP) on the cell membrane in NTCP-complemented HepG2cells,and with annexin II in the cytosol of HepG2and HepG2.2.15cells. And annexin IIcolocalized with HBsAg in the cytosol of HepG2.2.15cells.
In conclusion, our findings demonstrated that high expression of beta2-GPIenhances HBsAg binding to cell surfaces, thus contributing to virus particle transfer to theNTCP receptor and interaction with annexin II for viral binding and membrane fusion. Theyprovide new insights into the route of human HBV entry into hepatocytes.
引文
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