Abstract：
Fucosyltransferase 8 (Fut8) and core fucosylation play critical roles in regulating various biological processes, including immune response, signal transduction, proteasomal degradation, and energy metabolism. However, the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown. We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells (aNSPCs) and postnatal brain development. Fut8 depletion reduces the proliferation of aNSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo, respectively. Additionally, Fut8 deficiency impairs learning and memory in mice. Mechanistically, Fut8 directly interacts with integrin α6 (Itga6), an upstream regulator of the PI3k-Akt signaling pathway, and catalyzes core fucosylation of Itga6. Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6. Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway. Moreover, the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency. In summary, our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.
摘要：
岩藻糖基转移酶8（Fut8）和核心岩藻糖基化在调节各种生物过程中发挥关键作用，包括免疫反应，信号转导，蛋白酶体退化，和能量代谢。然而,Fut8和核心岩藻糖基化在调节成人神经发生中的功能和潜在机制尚不清楚。我们已经表明，Fut8和核心岩藻糖基化在成年神经干/祖细胞（aNSPCs）分化和出生后脑发育过程中显示出动态特征。Fut8耗竭在体外和体内减少aNSPCs的增殖并抑制aNSPCs的神经元分化，分别。此外,Fut8缺乏会损害小鼠的学习和记忆。机械上,Fut8直接与整合素α6（Itga6）相互作用，PI3k-Akt信号通路的上游调节因子，并催化Itga6的核心岩藻糖基化。Fut8的缺失通过促进泛素连接酶Trim21与Itga6的结合来增强Itga6的泛素化。低水平的Itga6抑制PI3K/Akt信号通路的活性。此外，Akt激动剂SC79可以挽救由Fut8缺乏引起的神经源性和行为缺陷。总之,我们的研究揭示了Fut8和核心岩藻糖基化在调节成人神经发生方面的基本功能，并阐明了潜在的机制。
