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RNF220 介导的 K63 连接多泛素化稳定少突胶质细胞发育和髓鞘形成过程中的 Olig 蛋白。

RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination.

机构信息

State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.

Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650223, China.

出版信息

Sci Adv. 2024 Feb 9;10(6):eadk3931. doi: 10.1126/sciadv.adk3931. Epub 2024 Feb 7.

DOI:10.1126/sciadv.adk3931
PMID:38324685
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10849602/
Abstract

Maldevelopment of oligodendroglia underlies neural developmental disorders such as leukodystrophy. Precise regulation of the activity of specific transcription factors (TFs) by various posttranslational modifications (PTMs) is required to ensure proper oligodendroglial development and myelination. However, the role of ubiquitination of these TFs during oligodendroglial development is yet unexplored. Here, we find that RNF220, a known leukodystrophy-related E3 ubiquitin ligase, is required for oligodendroglial development. RNF220 depletion in oligodendrocyte lineage cells impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, which consequently leads to learning and memory defects. Mechanistically, RNF220 targets Olig1/2 for K63-linked polyubiquitination and stabilization during oligodendroglial development. Furthermore, in a knock-in mouse model of leukodystrophy-related RNF220 mutation, the ubiquitination and stabilization of Olig proteins are deregulated in oligodendroglial cells. This results in pathomimetic oligodendroglial developmental defects, impaired myelination, and abnormal behaviors. Together, our evidence provides an alternative insight into PTMs of oligodendroglial TFs and how this essential process may be implicated in the etiology of leukodystrophy.

摘要

少突胶质细胞的发育不良是神经发育障碍（如白质营养不良）的基础。各种翻译后修饰（PTMs）精确调节特定转录因子（TFs）的活性对于确保适当的少突胶质细胞发育和髓鞘形成是必需的。然而，这些 TF 泛素化在少突胶质细胞发育过程中的作用尚未被探索。在这里，我们发现 RNF220（一种已知的与白质营养不良相关的 E3 泛素连接酶）是少突胶质细胞发育所必需的。在少突胶质细胞谱系细胞中耗尽 RNF220 会阻碍少突胶质前体细胞的增殖、分化和（再）髓鞘形成，从而导致学习和记忆缺陷。从机制上讲，RNF220 靶向 Olig1/2 进行 K63 连接多泛素化和稳定，以促进少突胶质细胞发育。此外，在与白质营养不良相关的 RNF220 突变的敲入小鼠模型中，少突胶质细胞中的 Olig 蛋白的泛素化和稳定被失调。这导致了类病的少突胶质细胞发育缺陷、髓鞘形成受损和异常行为。总之，我们的证据为少突胶质细胞 TF 的 PTM 提供了另一种见解，以及这一重要过程如何与白质营养不良的病因学有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d12f/10849602/f442e73256a4/sciadv.adk3931-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d12f/10849602/f442e73256a4/sciadv.adk3931-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d12f/10849602/6dbb647952b9/sciadv.adk3931-f1.jpg
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