The molecular basis of LST-1 self-renewal activity and its control of stem cell pool size
The molecular basis of LST-1 self-renewal activity and its control of stem cell pool size
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DOI：
10.1242/dev.181644
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发表时间：
2019-10-01
期刊：
影响因子：
4.6
通讯作者：
Kimble, Judith
中科院分区：
文献类型：
--
作者：
Haupt, Kimberly A.;Enright, Amy L.;Kimble, Judith
PUF RNA结合蛋白在动物发育中具有多种作用，在干细胞中具有广泛保守的作用。两种典型的PUF蛋白，FBF-1和FBF-2，促进C.秀丽隐杆线虫生殖系LST-1蛋白是自我更新的关键调节因子，当错误表达时是致癌的。在这里，我们证明了LST-1的自我更新活动驻留在一个预测的无序区域，窝藏两个KXXL基序。我们发现KXXL基序介导LST-1与FBF的结合，并且这些基序的点突变废除了LST-1的自我更新活性。因此，LST-1-FBF伙伴关系对于干细胞维持至关重要，并且是FBF调控网络中的关键要素。LST-1内的独特区域决定其空间表达和GSC池的大小。最重要的是，对富含IDR的蛋白质如何与保守的干细胞调节因子和RNA结合蛋白质在重要伙伴关系中起作用的分子理解表明了组合控制的广阔新途径。
PUF RNA-binding proteins have diverse roles in animal development, with a broadly conserved role in stem cells. Two paradigmatic PUF proteins, FBF-1 and FBF-2, promote both self-renewal and differentiation in the C. elegans germline. The LST-1 protein is a pivotal regulator of self-renewal and is oncogenic when mis-expressed. Here, we demonstrate that LST-1 self-renewal activity resides within a predicted disordered region that harbors two KXXL motifs. We find that the KXXL motifs mediate the binding of LST-1 to FBF, and that point mutations of these motifs abrogate LST-1 self-renewal activity. The LST-1-FBF partnership is therefore crucial to stem cell maintenance and is a key element in the FBF regulatory network. A distinct region within LST-1 determines its spatial expression and size of the GSC pool. Most importantly, the molecular understanding of how an IDR-rich protein works in an essential partnership with a conserved stem cell regulator and RNA-binding protein suggests broad new avenues for combinatorial control.