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蛋白质组学研究神经干细胞向少突胶质前体细胞分化揭示了 Dclk1 的磷酸化依赖性加工。

Proteomic investigation of neural stem cell to oligodendrocyte precursor cell differentiation reveals phosphorylation-dependent Dclk1 processing.

机构信息

Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Nussallee 11, 53115, Bonn, Germany.

Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach, Germany.

出版信息

Cell Mol Life Sci. 2023 Aug 18;80(9):260. doi: 10.1007/s00018-023-04892-8.

DOI:10.1007/s00018-023-04892-8
PMID:37594553
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10439241/
Abstract

Oligodendrocytes are generated via a two-step mechanism from pluripotent neural stem cells (NSCs): after differentiation of NSCs to oligodendrocyte precursor/NG2 cells (OPCs), they further develop into mature oligodendrocytes. The first step of this differentiation process is only incompletely understood. In this study, we utilized the neurosphere assay to investigate NSC to OPC differentiation in a time course-dependent manner by mass spectrometry-based (phospho-) proteomics. We identify doublecortin-like kinase 1 (Dclk1) as one of the most prominently regulated proteins in both datasets, and show that it undergoes a gradual transition between its short/long isoform during NSC to OPC differentiation. This is regulated by phosphorylation of its SP-rich region, resulting in inhibition of proteolytic Dclk1 long cleavage, and therefore Dclk1 short generation. Through interactome analyses of different Dclk1 isoforms by proximity biotinylation, we characterize their individual putative interaction partners and substrates. All data are available via ProteomeXchange with identifier PXD040652.

摘要

少突胶质细胞是由多能神经干细胞（NSCs）通过两步机制产生的：NSCs 分化为少突胶质前体细胞/NG2 细胞（OPCs）后，进一步发育为成熟的少突胶质细胞。这一分化过程的第一步仅部分被理解。在这项研究中，我们利用神经球测定法，通过基于质谱的（磷酸化）蛋白质组学，在时间依赖性的基础上研究 NSC 向 OPC 的分化。我们发现双皮质素样激酶 1（Dclk1）是两个数据集内调节最显著的蛋白之一，并表明它在 NSC 向 OPC 分化过程中其短/长异构体之间经历逐渐转变。这是通过其富含 SP 的区域的磷酸化来调节的，导致蛋白水解 Dclk1 长切割的抑制，从而产生 Dclk1 短。通过邻近生物素化对不同 Dclk1 异构体的互作组分析，我们鉴定了它们各自的潜在互作伙伴和底物。所有数据均可通过 ProteomeXchange 以标识符 PXD040652 获取。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/e3c8f65d79b2/18_2023_4892_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/95f6a6c036d0/18_2023_4892_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/439d02aa422a/18_2023_4892_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/bbad10962205/18_2023_4892_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/8802cbac2b4d/18_2023_4892_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/9af65459c2d1/18_2023_4892_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/e3c8f65d79b2/18_2023_4892_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/95f6a6c036d0/18_2023_4892_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/439d02aa422a/18_2023_4892_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/bbad10962205/18_2023_4892_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/8802cbac2b4d/18_2023_4892_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/9af65459c2d1/18_2023_4892_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0881/11072964/e3c8f65d79b2/18_2023_4892_Fig6_HTML.jpg

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