The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking.
The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking.
复制标题
逆转录酶复合物通过调节Notch受体运输来防止神经祖细胞衍生的肿瘤发生
作者：
Li B;Wong C;Gao SM;Zhang R;Sun R;Li Y;Song Y
单向Notch信号的正确建立和维持对各种干细胞系的稳态至关重要。然而，阻止细胞自主异位Notch信号激活和有害细胞命运决定的分子机制尚不清楚。本研究表明，在果蝇神经母细胞谱系中，逆转录复合物直接特异性调节Notch受体逆行运输，以确保从神经祖细胞到神经母细胞的单向Notch信号传导。E3泛素连接酶Itch/Su（dx）介导的Notch多泛素化在神经祖细胞中是固有的低效的，依赖于逆转录物介导的运输来避免Notch的异常内体积累和细胞自主信号激活。在逆转录酶功能障碍时，低泛素化的Notch积聚在Rab7+扩大的核内体中，在那里它被异位加工并以配体依赖的方式激活，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，即逆转录物及时检索潜在有害的Notch受体，以防止异常Notch激活诱导的神经祖细胞去分化和脑肿瘤形成。
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 Drosophila 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.