The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China.
The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China.
Sci China Life Sci. 2024 Jul;67(7):1427-1440. doi: 10.1007/s11427-023-2510-0. Epub 2024 Mar 22.
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.
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起着关键作用，包括免疫反应、信号转导、蛋白酶体降解和能量代谢。然而，Fut8 和核心岩藻糖基化在调节成年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细胞/祖细胞（aNSPCs）的分化和出生后大脑发育过程中呈现动态特征。Fut8 的耗竭减少了 aNSPCs 的增殖，并分别抑制了 aNSPCs 的体外和体内神经元分化。此外，Fut8 缺陷会损害小鼠的学习和记忆。在机制上，Fut8 直接与整合素 α6（Itga6）相互作用，Itga6 是 PI3k-Akt 信号通路的上游调节剂，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。Itga6 的低水平抑制了 PI3K/Akt 信号通路的活性。此外，Akt 激动剂 SC79 可以挽救 Fut8 缺失引起的神经发生和行为缺陷。总之，我们的研究揭示了 Fut8 和核心岩藻糖基化在调节成年神经发生中的重要功能，并阐明了潜在的机制。
