Translocated in liposarcoma regulates the ditrubution and funciton of mammalian enabled, a modulator of actin dynamics
Translocated in liposarcoma regulates the ditrubution and funciton of mammalian enabled, a modulator of actin dynamics
复制标题
脂肪肉瘤中的易位调节哺乳动物启用的分布和功能，肌动蛋白动力学的调节剂
作者：
Sugiura T;Matsuda S;Kurosaka S;Nakai N;Fukumoto K;Takahashi T;Maruyama H;Imaizumi K;Matsumoto M;Takumi T
易位脂肉瘤/融合肉瘤（TLS/FUS）是一种RNA结合蛋白，可调节mRNA转录物的剪接模式，已知可导致一种家族性肌萎缩性侧索硬化症（ALS）。在缺乏TLS的情况下，肌动蛋白调控蛋白Mena（哺乳动物激活蛋白）会优先进行选择性剪接。在本研究中，我们发现TLS的消融会导致Mena的亚细胞定位和功能失调。当TLS敲除（KO）小鼠胚胎成纤维细胞（mef）转染野生型Mena时，它不再在局灶粘连和外周结构中积累，而替代剪接形式的定位得以维持。此外，Mena抑制细胞运动的能力在TLS KO mef中丧失。此外，Mena不能促进TLS KO原代神经元的神经突生长。综上所述，TLS密切参与成纤维细胞和神经元中Mena周围的局部细胞骨架动力学。TLS KO细胞中Mena的失调所表明的细胞骨架动力学的强劲变化，为某些类型的ALS的发病机制提供了新的见解。
Translocated in liposarcoma/fused in sarcoma (TLS/FUS) is an RNA‐binding protein that regulates the splicing pattern of mRNA transcripts and is known to cause a type of familial amyotrophic lateral sclerosis (ALS). In the absence of TLS, Mammalian enabled (Mena), an actin‐regulatory protein and a target of TLS, undergoes preferential alternative splicing. In the present study, we show that the ablation of TLS dysregulates the subcellular location and functions of Mena. When TLS knockout (KO) mouse embryonic fibroblasts (MEFs) were transfected with wild‐type Mena, it no longer accumulated at focal adhesions and peripheral structures, whereas the localization of the alternatively spliced form was maintained. Additionally, the ability of Mena to suppress the motility of cells was lost in TLS KO MEFs. Moreover, Mena failed to promote neurite outgrowth in TLS KO primary neurons. Taken together, TLS is intimately involved in the local cytoskeletal dynamics surrounding Mena in both fibroblasts and neurons. The robust change in cytoskeletal dynamics, as indicated by the dysregulation of Mena in TLS KO cells, provides a new insight into the pathogenesis of certain types of ALS.