Affinity-Driven Site-Specific High Mannose Modification Determines the Structural Polymerization and Function of Tetrameric IgM in a Primitive Vertebrate.
Affinity-Driven Site-Specific High Mannose Modification Determines the Structural Polymerization and Function of Tetrameric IgM in a Primitive Vertebrate.
复制标题
亲和力驱动的位点特异性高甘露糖修饰决定了原始脊椎动物中四聚体 IgM 的结构聚合和功能。
DOI：
10.4049/jimmunol.2100921
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Jianmin Ye
中科院分区：
文献类型：
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作者：
Xiaoxue Yin;Xiaoyu Li;Liangliang Mu;Hao Bai;Yanjian Yang;Nuo Chen;Liting Wu;Shengli Fu;Jun Li;Wantao Ying;Jianmin Ye
硬骨四聚体IgM是免疫系统中最主要的免疫球蛋白，在宿主抵御微生物感染中发挥着重要作用。由于单体亚基的可变二硫键聚合，四聚体IgM具有相当大的结构多样性。以往的工作表明，硬骨IgM H链被复合型N-糖链完全占据。然而，经三硝基苯基(TNP)Ag攻击后，尼罗罗非鱼IgM H链ASN-509位的复杂N-糖链转变为高甘露糖。因此，本研究旨在研究罗非鱼IgM中亲和力相关的高甘露糖修饰的功能作用。罗非鱼对TNP的特异性IgM抗体亲和力成熟。TNP特异性IgM亲和力与其异构体结构的二硫键聚合水平呈正相关。质谱学分析表明，IgM亲和力与二硫键聚合的关系与ASN-509位点特异性的高甘露糖修饰有关。此外，高甘露糖含量的增加促进了吞噬细胞表面的IgM和甘露糖受体(MR)的结合。此外，据我们所知，IgM和MR的相互作用增强了吞噬细胞对无乳链球菌的吞噬能力，本研究证明了位点特异性的高甘露糖修饰与IgM抗体的亲和力及其结构二硫键聚合有关，并通过IgM和MR的结合放大了吞噬细胞的吞噬能力。本研究为理解免疫系统进化过程中IgM结构和功能的关联提供了证据。
Teleost tetramer IgM is the predominant Ig in the immune system and plays essential roles in host defense against microbial infection. Due to variable disulfide polymerization of the monomeric subunits, tetrameric IgM possesses considerable structural diversity. Previous work indicated that the teleost IgM H chain was fully occupied with complex-type N-glycans. However, after challenge with trinitrophenyl (TNP) Ag, the complex N-glycans in the Asn-509 site of Oreochromis niloticus IgM H chain transformed into high mannose. This study, therefore, was conducted to examine the functional roles of the affinity-related high-mannose modification in tilapia IgM. The TNP-specific IgM Ab affinity maturation was revealed in tilapia over the response. A positive correlation between TNP-specific IgM affinity and its disulfide polymerization level of isomeric structure was demonstrated. Mass spectrometric analysis indicated that the relationship between IgM affinity and disulfide polymerization was associated with the Asn-509 site-specific high-mannose modification. Furthermore, the increase of high mannose content promoted the combination of IgM and mannose receptor (MR) on the surface of phagocytes. Moreover, the increased interaction of IgM and MR amplified the phagocytic ability of phagocytes to Streptococcus agalactiae To our knowledge, this study demonstrates that site-specific high-mannose modification associates with IgM Ab affinity and its structural disulfide polymerization and amplifies the phagocytosis of phagocytes by the combination of IgM and MR. The present study provides evidence for understanding the association of IgM structure and function during the evolution of the immune system.