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Xiaoliu LI, Xinhao YAN, Zhiwei LI, Hua CHEN, Pingzhu ZHANG,
《化学科学与工程前沿（英文）》 2010年 第4卷 第3期 页码 342-347 doi: 10.1007/s11705-009-0279-1
关键词： photoelectron spectroscopy adsorption-desorption glycosylation deactivated diffraction
Emerging roles of podoplanin in vascular development and homeostasis
null
《医学前沿（英文）》 2015年 第9卷 第4期 页码 421-430 doi: 10.1007/s11684-015-0424-9
Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on LECs or FRCs activates CLEC-2 in platelets, triggering platelet activation and/or aggregation through downstream signaling events, including activation of Syk kinase. This mechanism is required to initiate and maintain separation of blood and lymphatic vessels and to stabilize high endothelial venule integrity within lymph nodes. In the vascular system, normal expression of PDPN at the LEC surface requires transcriptional activation of Pdpn by Prox1 and modification of PDPN with core 1-derived O-glycans. This review provides a comprehensive overview of the roles of PDPN in vascular development and lymphoid organ maintenance and discusses the mechanisms that regulate PDPN expression related to its function.
关键词： podoplanin CLEC-2 Prox1 O-glycosylation lymphatic vascular development and maintenance lymphoid organ homeostasis
IgG N-糖基心血管年龄独立于真实年龄精准表征心血管事件风险 Article
武志远, 郭政, 郑雨露, 王玉涛, 张海平, 潘慧颖, 李志伟, Lois Balmer, 李霞, 陶丽新, 郭秀花, 王嵬
《工程（英文）》 2023年 第26卷 第7期 页码 99-107 doi: 10.1016/j.eng.2022.12.004
亚临床动脉粥样硬化和代谢紊乱是心血管健康的重要风险因素，应用免疫球蛋白G（IgG）N-聚糖模式作为炎症指标表征其发病风险已有研究报道。然而，对于IgG N-糖基谱在心血管疾病（CVD）风险分层中的能力仍然未知。本研究旨在利用IgG N-糖基标志物开发追踪心血管疾病风险的年龄指数。本研究基于横断面调查，从Busselton健康和老龄研究中共招募1465名40~70岁之间的个体。使用机器学习递归特征消除和惩罚回归算法逐步筛选特征糖基，并开发IgG N-糖基化心血管年龄（GlyCage）指数，以反映归因于心血管风险的与真实年龄间的偏差。结果显示，对GlyCage指数贡献最大的是具有双分叉N-乙酰葡萄糖胺（GlcNAc）的岩藻糖基化N-聚糖（GP6, FA2B）和具有双分叉GlcNAc的双半乳糖基化N-聚糖（GP13, A2BG2）。GlyCage独立于真实年龄，与较高的Framingham十年心血管风险[优势比（OR）为1.09；95% CI: 1.05~1.13]和患心血管疾病概率（OR, 1.07; 95% CI: 1.01~1.13）显著相关。GlyCage大于真实年龄三年及以上的个体，其心血管风险和心血管疾病患病概率增加，调整后的OR值分别为2.22（95% CI：1.41~3.53）和2.71（95% CI: 1.25~6.41）。GlyCage指数区分十年心血管风险和事件的ROC曲线下面积（AUC）值分别为0.73和0.65，而真实年龄为0.65和0.63。因此，本研究开发的GlyCage指数利用IgG N-糖基谱追踪心血管健康水平。GlyCage和真实年龄之间的差距能够独立地表征心血管风险，提示IgG N-糖基化在心血管疾病的发病机制中起作用。GlyCage指数对心血管风险的预测能力需要在其他人群中进行外部和纵向验证。
人类蛋白质N-糖基化的十二年全基因组关联研究 Review
Anna Timoshchuk, Sodbo Sharapov, Yurii S. Aulchenko
《工程（英文）》 2023年 第26卷 第7期 页码 17-31 doi: 10.1016/j.eng.2023.03.013
Most human-secreted and membrane-bound proteins have covalently attached oligosaccharide chains, or glycans. Glycosylation influences the physical and chemical properties of proteins, as well as their biological functions. Unsurprisingly, alterations in protein glycosylation have been implicated in a growing number of human diseases, and glycans are increasingly being considered as potential therapeutic targets, an essential part of therapeutics, and biomarkers. Although glycosylation pathways are biochemically well-studied, little is known about the networks of genes that guide the cell- and tissue-specific regulation of these biochemical reactions in humans in vivo. The lack of a detailed understanding of the mechanisms regulating glycome variation and linking the glycome to human health and disease is slowing progress in clinical applications of human glycobiology. Two of the tools that can provide much sought-after knowledge of human in vivo glycobiology are human genetics and genomics, which offer a powerful data-driven agnostic approach for dissecting the biology of complex traits. This review summarizes the current state of human populational glycogenomics. In Section 1, we provide a brief overview of the N-glycan's structural organization, and in Section 2, we give a description of the major blood plasma glycoproteins. Next, in Section 3, we summarize, systemize, and generalize the results from current N-glycosylation genome-wide association studies (GWASs) that provide novel knowledge of the genetic regulation of the populational variation of glycosylation. Until now, such studies have been limited to an analysis of the human blood plasma N-glycome and the N-glycosylation of immunoglobulin G and transferrin. While these three glycomes make up a rather limited set compared with the enormous multitude of glycomes of different tissues and glycoproteins, the study of these three does allow for powerful analysis and generalization. Finally, in Section 4, we turn to genes in the established loci, paying particular attention to genes with strong support in Section 5. At the end of the review, in Sections 6 and 7, we describe special cases of interest in light of new discoveries, focusing on possible mechanisms of action and biological targets of genetic variation that have been implicated in human protein N-glycosylation.
流感与COVID-19患者的免疫球蛋白G糖基化差异 Article
Marina Kljaković-Gašpić Batinjan, Tea Petrović, Frano Vučković, Irzal Hadžibegović, Barbara Radovani, Ivana Jurin, Lovorka Đerek, Eva Huljev, Alemka Markotić, Ivica Lukšić, Irena Trbojević-Akmačić, Gordan Lauc, Ivan Gudelj, Rok Čivljak
《工程（英文）》 2023年 第26卷 第7期 页码 54-62 doi: 10.1016/j.eng.2022.08.007
The essential role of immunoglobulin G (IgG) in immune system regulation and combatting infectious diseases cannot be fully recognized without an understanding of the changes in its N-glycans attached to the asparagine 297 of the Fc domain that occur under such circumstances. These glycans impact the antibody stability, half-life, secretion, immunogenicity, and effector functions. Therefore, in this study, we analyzed and compared the total IgG glycome—at the level of individual glycan structures and derived glycosylation traits (sialylation, galactosylation, fucosylation, and bisecting N-acetylglucosamine (GlcNAc))—of 64 patients with influenza, 77 patients with coronavirus disease 2019 (COVID-19), and 56 healthy controls. Our study revealed a significant decrease in IgG galactosylation, sialylation, and bisecting GlcNAc (where the latter shows the most significant decrease) in deceased COVID-19 patients, whereas IgG fucosylation was increased. On the other hand, IgG galactosylation remained stable in influenza patients and COVID-19 survivors. IgG glycosylation in influenza patients was more time-dependent: In the first seven days of the disease, sialylation increased and fucosylation and bisecting GlcNAc decreased; in the next 21 days, sialylation decreased and fucosylation increased (while bisecting GlcNAc remained stable). The similarity of IgG glycosylation changes in COVID-19 survivors and influenza patients may be the consequence of an adequate immune response to enveloped viruses, while the observed changes in deceased COVID-19 patients may indicate its deviation.
免疫球蛋白G N-糖基化与代谢特征之间的双向因果关联——一项孟德尔随机化研究 Article
孟晓妮, 曹维杰, 刘迪, Isinta Elijah Maranga, 邢薇佳, 侯海峰, 徐希柱, 宋曼殳, 王友信
《工程（英文）》 2023年 第26卷 第7期 页码 74-88 doi: 10.1016/j.eng.2022.11.004
既往研究已发现免疫球蛋白 G（immunoglobulin G, IgG）N-糖基化与代谢特征之间存在关联，但它们之间是否存在因果关联尚有待研究。本研究使用孟德尔随机化（Mendelian randomization, MR）研究方法整合全基因组关联研究（genome-wide association studies, GWAS）和数量性状基因座（quantitative trait loci, QTL）数据探究IgG N-糖基化与代谢特征之间的双向因果关联。在正向MR分析中，通过整合IgG N-糖基-QTL遗传变异与GWAS 数据和代谢特征进行分析，分别发现59个包括影响体质指数（body mass index, BMI）的9个IgG N-糖基（glycan peaks, GP）（GP1和GP6等）和影响空腹血糖（fasting plasma glucose, FPG）的 7个IgG N-糖基（GP1和GP5等）以及15个[包括影响BMI 的5个IgG N-糖基（GP2 和 GP11 等）和影响FPG的 4个IgG N-糖基（GP1和GP10等）]由遗传决定的 IgG N-糖基在单样本和两样本MR研究中与代谢特征存在因果关联（全部 P < 0.05）。相应地，对整合代谢特征-QTL-遗传变异与GWAS结果和 IgG N-糖基进行MR分析的结果显示，在单样本和两样本MR研究中，分别发现72个包括影响GP1的1个因果代谢特征[高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL-C）]和影响GP2的5个因果代谢特征[FPG、收缩压（systolic blood pressure, SBP）等]和4个[包括影响GP3的1个因果代谢特征（HDL-C）和影响 GP9 的1个代谢特征（HDL-C）]由遗传决定的代谢特征与 IgG N-糖基之间存在因果关联（全部 P < 0.05）。值得注意的是，在单样本和两样本的MR分析中均发现了遗传决定的高水平的GP11与BMI水平增高存在因果关联[固定效应模型-Beta (SE): 0.106 (0.034) 和 0.010 (0.005)]和高水平的HDL-C与 GP9 水平降低存在因果关联[−0.071 (0.022) 和−0.306 (0.151)]，且这一结果在单样本和两样本的 meta汇总分析中得到了进一步验证[固定效应模型-Beta（95%置信区间）分别为：0.0109 (0.0012, 0.0207) 和−0.0759 (−0.1186, −0.0332)]。综上所述，本研究全面的双向MR分析提供了IgG N-糖基化与代谢特征之间双向因果关联的证据，在一定程度上揭示了 IgG N-糖基化与代谢特征之间的生物学机制。
月经周期中免疫球蛋白G N-糖基化的周期性变化 Article
Julija Jurić, Hongli Peng, Manshu Song, Frano Vučković, Jelena Šimunović, Irena Trbojević-Akmačić, Youxin Wang, Jiaonan Liu, Qing Gao, Hao Wang, Qiaoyun Chu, Marija Pezer, Wei Wang, Gordan Lauc
《工程（英文）》 2023年 第26卷 第7期 页码 108-118 doi: 10.1016/j.eng.2022.10.020
Immunoglobulin G (IgG) is the most abundant plasma glycoprotein and a prominent humoral immune mediator. Glycan composition affects the affinity of IgG to ligands and consequent immune responses. The modification of IgG N-glycosylation is considered to be one of the various mechanisms by which sex hormones modulate the immune system. Although the menstrual cycle is the central sex hormone-related physiological process in most women of reproductive age, IgG N-glycosylation dynamics during the menstrual cycle have not yet been investigated. To fill this gap, we profiled the plasma IgG N-glycans of 70 healthy premenopausal women at 12 time points during their menstrual cycles (every 7 days for 3 months) using hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC). We observed cyclic periodic changes in the N-glycosylation of IgG in association with the menstrual cycle phase and sex hormone concentration in plasma. On the integrated cohort level, the modeled average menstrual cycle effect on the abundance of IgG N-glycosylation traits was low for each trait, with the highest being 1.1% for agalactosylated N-glycans. However, intrapersonal changes were relatively high in some cases; for example, the largest difference between theminimum and maximum values during themenstrual cycle was up to 21% for sialylated N-glycans. Across all measurements, the menstrual cycle phase could explain up to 0.72% of the variation in the abundance of a single IgG glycosylation trait of monogalactosylation. In contrast, up to 99% of the variation in the abundance of digalactosylation could be attributed to interpersonal differences in IgG N-glycosylation. In conclusion, the average extent of changes in the IgG N-glycopattern that occur during the menstrual cycle is small; thus, the IgG N-glycoprofiling of women in large sample-size studies can be performed regardless of menstrual cycle phase.
《医学前沿（英文）》 2022年 第16卷 第3期 页码 322-338 doi: 10.1007/s11684-021-0901-2
关键词： cancer immunotherapy chimeric antigen receptor solid tumors tumor-associated antigen glycosylation O-glycans adoptive cell therapy
Hui Xue, Dike Tao, Yuteng Weng, Qiqi Fan, Shuang Zhou, Ruilin Zhang, Han Zhang, Rui Yue, Xiaogang Wang, Zuolin Wang, Yao Sun
《医学前沿（英文）》 2019年 第13卷 第5期 页码 575-589 doi: 10.1007/s11684-019-0693-9
关键词： fracture extracellular matrix dentin matrix protein 1 proteoglycan cartilage
基于正交质谱的N-糖组谱揭示哈夫病潜在病原学 Article
刘思, 刘圆圆, 林佳静, 刘笔锋, 何振宇, 吴晓旻, 刘欣
《工程（英文）》 2023年 第26卷 第7期 页码 63-73 doi: 10.1016/j.eng.2022.09.012
食用煮熟的小龙虾可能导致哈夫病（HD），该病被认为是由不明毒素引起的，而病因尚不清楚。N-糖组的剖析将促进破译疾病的分子机制，而HD相关的糖基化从未被探索过。2019—2020年期间，本研究团队招募了来自武汉市疾病预防控制中心的90份HD患者和对照组血清样本。本文中，采用基于高通量的正交质谱对HD中血清和血清衍生的IgG的N-糖组谱进行了表征。数据显示，HD与总血清糖蛋白的核心岩藻糖基化和单半乳糖醇化升高有关。血清IgG水平是HD患者的良好指标。此外，IgG的差异半乳糖基化和唾液酸化与HD密切相关。值得注意的是，IgG1和IgG2的半乳糖基化和唾液酸化的变化具有亚类特异性。有意义的是，IgG2或IgG3/4的唾液酸化和半乳糖基化改变与HD的临床标志物密切相关。本研究表明差异化IgG N-糖基化与HD的关联，为这种罕见疾病的病因提供了新的见解。
人体前列腺特异性抗原携带含酮基-脱氧壬酮糖酸的N-聚糖 Article
Wei Wang, Tao Zhang, Jan Nouta, Peter A. van Veelen, Noortje de Haan, Theo M. de Reijke, Manfred Wuhrer, Guinevere S.M. Lageveen-Kammeijer
《工程（英文）》 2023年 第26卷 第7期 页码 119-131 doi: 10.1016/j.eng.2023.02.009
Ketodeoxynononic acid (Kdn) is a rather uncommon class of sialic acid in mammals. However, associations have been found between elevated concentrations of free or conjugated Kdn in relation to human cancer progression. Hitherto, there has been a lack of conclusive evidence that Kdn occurs on (specific) human glycoproteins (conjugated Kdn). Here, we report for the first time that Kdn is expressed on prostate-specific antigen (PSA) N-linked glycans derived from human seminal plasma and urine. Interestingly, Kdn was found only in an α2,3-linkage configuration on an antennary galactose, indicating a highly specific biosynthesis. This unusual glycosylation feature was also identified in a urinary PSA cohort in relation to prostate cancer (PCa), although no differences were found between PCa and non-PCa patients. Further research is needed to investigate the occurrence, biosynthesis, biological role, and biomarker potential of both free and conjugated Kdn in humans.
新型冠状病毒HCoV-19 S蛋白与人ACE2蛋白表面糖链和独特翻译后修饰的质谱分析 Article
孙泽宇, 任科燚, 张兴, 陈景华, 姜正一, 江静, 季飞洋, 欧阳晓希, 李兰娟
《工程（英文）》 2021年 第7卷 第10期 页码 1441-1451 doi: 10.1016/j.eng.2020.07.014
当下新型冠状病毒肺炎（COVID-19）的国际大流行促使全球科学家努力尝试揭秘新冠病毒HCoV-19的生物学特性。质谱分析（MS）发现，在HCoV-19 S蛋白的21个潜在糖基化修饰位点中，有20个位点完全被N-糖链占据，其糖型以低聚甘露糖为主。人血管紧张素转换酶2（hACE2）的7个糖基化位点完全被复合型N-糖链占据。然而，糖基化修饰并不能直接影响HCoV-19 S蛋白与hACE2之间的结合亲和力。另外，我们还发现了S蛋白和hACE2的多个甲基化修饰位点，以及hACE2的多个羟脯氨酸修饰位点。通过在最近发表的冷冻电镜（cryo-EM）结构的基础上加入N-糖链和蛋白质翻译后修饰（PTM），我们构建了HCoV-19 S蛋白和hACE2的精细结构模型。本研究揭示的HCoV-19 S蛋白和hACE2的PTM及糖基化图谱为研究病毒的宿主黏附、免疫反应，以及相关药物和疫苗的研发提供了更多的蛋白质结构细节。
转录因子HNF1A、HNF4A和FOXA2调节肝细胞蛋白质N-糖基化 Article
Vedrana Vičić Bočkor,Nika Foglar,Goran Josipović,Marija Klasić,Ana Vujić,Branimir Plavša,Toma Keser,Samira Smajlović,Aleksandar Vojta,Vlatka Zoldoš
《工程（英文）》 2024年 第32卷 第1期 页码 58-69 doi: 10.1016/j.eng.2023.09.019
Hepatocyte nuclear factor 1 alpha (HNF1A), hepatocyte nuclear factor 4 alpha (HNF4A), and forkhead box protein A2 (FOXA2) are key transcription factors that regulate a complex gene network in the liver, creating a regulatory transcriptional loop. The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes. Our in silico analysis of HNF1A, HNF4A, and FOXA2 binding to the 10 candidate glyco-genes studied in this work confirms a significant enrichment of these transcription factors specifically in the liver. Our previous studies identified HNF1A as a master regulator of fucosylation, glycan branching, and galactosylation of plasma glycoproteins. Here, we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype. We used the state-of-the-art clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) molecular tool for the downregulation of the HNF1A, HNF4A, and FOXA2 genes in HepG2 cells—a human liver cancer cell line. The results show that the downregulation of all three genes individually and in pairs affects the transcriptional activity of many glyco-genes, although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures. The effect is better seen as an overall change in the total HepG2 N-glycome, primarily due to the extension of biantennary glycans. We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure. We also propose a model showing feedback loops with the mutual activation of HNF1A–FOXA2 and HNF4A–FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
关键词： Clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) Epigenetics Hepatocyte nuclear factor 1 alpha (HNF1A) Hepatocyte nuclear factor 4 alpha (HNF4A) Forkhead box protein A2 (FOXA2) N-glycosylation HepG2 cells
血清免疫球蛋白G N-糖基的高通量分析——一种消化道癌症的非侵入性生物标志物 Article
刘鹏程, 王小兵, 顿爱社, 李昱潼, 李厚强, 王璐, 张怡春, 李灿灿, 张金霞, 张晓雨, 马立兴, 侯海峰
《工程（英文）》 2023年 第26卷 第7期 页码 44-53 doi: 10.1016/j.eng.2023.02.008
免疫球蛋白G (Immunoglobulin G, IgG) 的 N-糖基化在炎症性疾病的发展中起着重要作用。本研究旨在评价IgG N-糖基在消化道癌症亚型中的诊断效能。从中国医学科学院肿瘤医院招募749名消化道癌症患者，包括食管癌 (esophageal cancer, EC)、胃癌 (gastric cancer, GC)、结直肠癌 (colorectal cancer, CRC) 和胰腺癌 (pancreatic cancer, PC) 患者。采用亲水交互高效液相色谱-超高效液相色谱（hydrophilic interaction liquid chromatography using ultra-performance liquid chromatography, HILIC-UPLC）分析血浆中IgG的 N-糖基构成。采用Bio-Plex悬液芯片系统检测方法（Bio-Rad）进行炎症因子检测。采用典型相关分析（canonical correlation analysis, CCA）探索糖基和炎症因子之间的相关性。 采用LASSO回归和logistic回归模型，基于检测到的糖基谱建立可用于区分胃肠癌症患者和健康人群诊断模型。与健康对照组相比，EC、GC、CRC和PC患者的唾液酸化和半乳糖基化水平降低，而二等分乙酰葡萄糖胺基化水平在消化道癌症患者中升高。 此外，只有胰腺癌患者具有低水平的岩藻糖基化。消化道癌症组的IL-1β、IL-31和sCD40L水平均高于对照组。IgG N-糖基的组成与炎症因子相关 (r = 0.556)。基于糖基的模型表现出良好的诊断效能，EC、GC、CRC和PC的受试者工作特征曲线下面积(AUC)分别为0.972、0.871、0.867和0.907。这些研究结果表明，IgG N-糖基在调节消化道肿瘤的发病机制中发挥了重要作用。血清IgG N-糖基可以作为潜在的非侵入性辅助消化道癌症临床诊断的方法。
标题 作者 时间 类型 操作
Catalysis and deactivation of montmorillonite K10 in the aryl O -glycosylation of glycosyl trichloroacetoimidates
Xiaoliu LI, Xinhao YAN, Zhiwei LI, Hua CHEN, Pingzhu ZHANG,
期刊论文
IgG N-糖基心血管年龄独立于真实年龄精准表征心血管事件风险
武志远, 郭政, 郑雨露, 王玉涛, 张海平, 潘慧颖, 李志伟, Lois Balmer, 李霞, 陶丽新, 郭秀花, 王嵬
期刊论文
流感与COVID-19患者的免疫球蛋白G糖基化差异
Marina Kljaković-Gašpić Batinjan, Tea Petrović, Frano Vučković, Irzal Hadžibegović, Barbara Radovani, Ivana Jurin, Lovorka Đerek, Eva Huljev, Alemka Markotić, Ivica Lukšić, Irena Trbojević-Akmačić, Gordan Lauc, Ivan Gudelj, Rok Čivljak
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