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SUMOylation 修饰丝氨酸苏氨酸激酶促进神经干细胞的重新激活。

SUMOylation of Warts kinase promotes neural stem cell reactivation.

机构信息

Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.

Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.

出版信息

Nat Commun. 2024 Oct 17;15(1):8557. doi: 10.1038/s41467-024-52569-y.

DOI:10.1038/s41467-024-52569-y
PMID:39419973
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11487185/
Abstract

A delicate balance between neural stem cell (NSC) quiescence and proliferation is important for adult neurogenesis and homeostasis. Small ubiquitin-related modifier (SUMO)-dependent post-translational modifications cause rapid and reversible changes in protein functions. However, the role of the SUMO pathway during NSC reactivation and brain development is not established. Here, we show that the key components of the SUMO pathway play an important role in NSC reactivation and brain development in Drosophila. Depletion of SUMO/Smt3 or SUMO conjugating enzyme Ubc9 results in notable defects in NSC reactivation and brain development, while their overexpression leads to premature NSC reactivation. Smt3 protein levels increase with NSC reactivation, which is promoted by the Ser/Thr kinase Akt. Warts/Lats, the core protein kinase of the Hippo pathway, can undergo SUMO- and Ubc9-dependent SUMOylation at Lys766. This modification attenuates Wts phosphorylation by Hippo, leading to the inhibition of the Hippo pathway, and consequently, initiation of NSC reactivation. Moreover, inhibiting Hippo pathway effectively restores the NSC reactivation defects induced by SUMO pathway inhibition. Overall, our study uncovered an important role for the SUMO-Hippo pathway during Drosophila NSC reactivation and brain development.

摘要

神经干细胞 (NSC) 的静止和增殖之间的微妙平衡对于成人神经发生和内稳态很重要。小泛素相关修饰物 (SUMO)-依赖性翻译后修饰会导致蛋白质功能的快速和可逆变化。然而，SUMO 途径在 NSC 再激活和大脑发育中的作用尚未确定。在这里，我们表明 SUMO 途径的关键成分在果蝇 NSC 再激活和大脑发育中发挥重要作用。SUMO/Smt3 或 SUMO 缀合酶 Ubc9 的耗尽会导致 NSC 再激活和大脑发育的明显缺陷，而过表达它们则会导致 NSC 过早再激活。Smt3 蛋白水平随 NSC 再激活而增加，这是由丝氨酸/苏氨酸激酶 Akt 促进的。Warts/Lats 是 Hippo 途径的核心蛋白激酶，可在 Lys766 处发生 SUMO 和 Ubc9 依赖性 SUMOylation。这种修饰可减弱 Hippo 对 Wts 的磷酸化，从而抑制 Hippo 途径，进而启动 NSC 再激活。此外，抑制 Hippo 途径可有效恢复 SUMO 途径抑制诱导的 NSC 再激活缺陷。总体而言，我们的研究揭示了 SUMO-Hippo 途径在果蝇 NSC 再激活和大脑发育中的重要作用。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11487185/b75f8754c6ca/41467_2024_52569_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11487185/90ebd9ec1991/41467_2024_52569_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11487185/01a6ec3de812/41467_2024_52569_Fig9_HTML.jpg
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