The role of TREM2 N-glycans in trafficking to the cell surface and signal transduction of TREM2
The role of TREM2 N-glycans in trafficking to the cell surface and signal transduction of TREM2
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TREM2 N-聚糖在运输至细胞表面和 TREM2 信号转导中的作用
DOI：
10.1093/jb/mvac073
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Iwata Nobuhisa
中科院分区：
文献类型：
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作者：
Shirotani Keiro;Hatta Daisuke;Wakita Naoki;Watanabe Kaori;Iwata Nobuhisa
髓样细胞上表达的触发受体2（TREM 2）的变体与阿尔茨海默病以及其他神经退行性疾病的发病率增加相关。TREM 2在体外和体内都是糖基化的，但这种修饰的意义尚不清楚。我们之前建立了一个敏感和特异性的报告细胞模型，涉及培养的Jurkat细胞稳定表达荧光素酶报告基因和编码TREM 2DAP 12融合蛋白的基因，以监测TREM 2依赖性信号传导。在本研究中，我们制备了修饰的报告细胞，以研究N20和N79处的N-聚糖的作用。我们表明N79处的N-聚糖在TREM 2易位到细胞表面中具有必要的作用，而N20和N79处的N-聚糖在细胞内信号转导中具有关键作用。我们的研究结果表明，TREM 2 N-聚糖的结构变化可能导致小胶质细胞功能障碍，这有助于神经退行性疾病的发病机制，并且保持TREM 2 N-糖基化和负责的糖基转移酶的完整性可能是治疗这些疾病的新的治疗策略。
Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer’s disease, as well as other neurodegenerative disorders. TREM2 is glycosylatedin vitroandin vivo, but the significance of the modification is unknown. We previously established a sensitive and specific reporter cell model involving cultured Jurkat cells stably expressing a luciferase reporter gene and a gene encoding a TREM2DAP12 fusion protein to monitor TREM2-dependent signalling. In the present study, we prepared modified reporter cells to investigate the role of the N-glycans at N20 and N79. We show that the N-glycans at N79 have a requisite role in translocation of TREM2 to the cell surface, while the N-glycans at both N20 and N79 have a critical role in intracellular signal transduction. Our results indicate that structural changes to the TREM2 N-glycans may cause microglial dysfunction that contributes to the pathogenesis of neurodegenerative disorders and that maintaining the integrity of TREM2 N-glycosylation and the responsible glycosyltransferases may be a novel therapeutic strategy to treat these disorders.