Endo-β-N-acetylglucosaminidases (ENGases) that specifically hydrolyze the Asn297-linked glycan on immunoglobulin G (IgG) antibodies, the major molecular determinant of fragment crystallizable (Fc) γ receptor (FcγR) binding, are exceedingly rare. All previously characterized IgG-specific ENGases are multi-domain proteins secreted as an immune evasion strategy by Streptococcus pyogenes strains. Here, using in silico analysis and mass spectrometry techniques, we identified a family of single-domain ENGases secreted by pathogenic corynebacterial species that exhibit strict specificity for IgG antibodies. By X-ray crystallographic and surface plasmon resonance analyses, we found that the most catalytically efficient IgG-specific ENGase family member recognizes both protein and glycan components of IgG. Employing in vivo models, we demonstrated the remarkable efficacy of this IgG-specific ENGase in mitigating numerous pathologies that rely on FcγR-mediated effector functions, including T and B lymphocyte depletion, autoimmune hemolytic anemia, and antibody-dependent enhancement of dengue disease, revealing its potential for treating and/or preventing a wide range of IgG-mediated diseases in humans.

中文翻译：

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IgG 特异性内切糖苷酶对 IgG 介导的病理的强效疗效


特异性水解免疫球蛋白 G （IgG） 抗体上 Asn297 连接的聚糖的 Endo-β-N-乙酰氨基葡萄糖苷酶 （ENGases） 极为罕见，免疫球蛋白 G （IgG） 抗体是片段可结晶 （Fc） γ受体 （FcγR） 结合的主要分子决定因素。所有先前表征的 IgG 特异性 ENGase 都是化脓性链球菌菌株作为免疫逃避策略分泌的多结构域蛋白。在这里，使用计算机分析和质谱技术，我们鉴定了由病原棒状杆菌物种分泌的单结构域 ENGase 家族，这些物种对 IgG 抗体表现出严格的特异性。通过 X 射线晶体学和表面等离子体共振分析，我们发现最具催化效率的 IgG 特异性 ENGase 家族成员可识别 IgG 的蛋白质和聚糖组分。采用 体内模型，我们证明了这种 IgG 特异性 ENGase 在缓解依赖于 FcγR 介导的效应子功能的多种病理方面的显着疗效，包括 T 和 B 淋巴细胞耗竭、自身免疫性溶血性贫血和登革热疾病的抗体依赖性增强，揭示了其治疗和/或预防多种 IgG 介导的人类疾病的潜力。