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逆向转运复合体通过调节 Notch 受体运输来防止神经祖细胞衍生的肿瘤发生。

The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking.

机构信息

Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.

State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China.

出版信息

Elife. 2018 Sep 4;7:e38181. doi: 10.7554/eLife.38181.

DOI:10.7554/eLife.38181
PMID:30176986
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6140715/
Abstract

The correct establishment and maintenance of unidirectional Notch signaling are critical for the homeostasis of various stem cell lineages. However, the molecular mechanisms that prevent cell-autonomous ectopic Notch signaling activation and deleterious cell fate decisions remain unclear. Here we show that the retromer complex directly and specifically regulates Notch receptor retrograde trafficking in neuroblast lineages to ensure the unidirectional Notch signaling from neural progenitors to neuroblasts. Notch polyubiquitination mediated by E3 ubiquitin ligase Itch/Su(dx) is inherently inefficient within neural progenitors, relying on retromer-mediated trafficking to avoid aberrant endosomal accumulation of Notch and cell-autonomous signaling activation. Upon retromer dysfunction, hypo-ubiquitinated Notch accumulates in Rab7 enlarged endosomes, where it is ectopically processed and activated in a ligand-dependent manner, causing progenitor-originated tumorigenesis. Our results therefore unveil a safeguard mechanism whereby retromer retrieves potentially harmful Notch receptors in a timely manner to prevent aberrant Notch activation-induced neural progenitor dedifferentiation and brain tumor formation.

摘要

正确建立和维持单向 Notch 信号对于各种干细胞谱系的内稳态至关重要。然而，防止细胞自主异位 Notch 信号激活和有害细胞命运决定的分子机制尚不清楚。在这里，我们表明，内体再循环复合物直接且特异性地调节神经母细胞谱系中 Notch 受体的逆行运输，以确保从神经祖细胞到神经母细胞的单向 Notch 信号。E3 泛素连接酶 Itch/Su(dx)介导的 Notch 多泛素化在神经祖细胞内固有地效率低下，依赖于内体再循环介导的运输来避免 Notch 的异常内体积累和细胞自主信号激活。在内体再循环功能障碍时，低泛素化的 Notch 在 Rab7 增大的内体中积累，在那里它以配体依赖的方式异位加工和激活，导致祖细胞起源的肿瘤发生。因此，我们的研究结果揭示了一种保护机制，即内体再循环及时回收潜在有害的 Notch 受体，以防止异常的 Notch 激活诱导的神经祖细胞去分化和脑肿瘤形成。

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