Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations.
Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations.
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DOI：
10.1093/nar/gkq1162
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发表时间：
2011-04
影响因子：
14.9
通讯作者：
Nukina N
中科院分区：
文献类型：
--
作者：
Kino Y;Washizu C;Aquilanti E;Okuno M;Kurosawa M;Yamada M;Doi H;Nukina N
TLS（translocated in liposarcoma），也称为FUS（fused in sarcoma），是一种RNA/DNA结合蛋白，在转录、前mRNA剪接和mRNA转运中起调节作用。TLS中的突变导致家族性肌萎缩侧索硬化症（ALS）6型。此外，在多聚谷氨酰胺疾病、散发性ALS、非SOD 1家族性ALS和额颞叶变性的子集中发现了含有TLS的细胞内包涵体，表明TLS在多种神经退行性疾病中具有病理学意义。在这里，我们确定了TLS结构域，确定细胞内定位的鼠TLS。其中，位于C-末端的PY-NLS是细胞内定位以及E1 A衍生的小基因的剪接调节的强决定因素。PY-NLS的破坏促进了与应激颗粒和P体部分重叠的细胞质颗粒的形成。一些与ALS相关的突变改变了TLS的细胞内定位和剪接调节，而大多数突变本身并不影响剪接调节。然而，丝氨酸505（或丝氨酸513在人类）的磷酸模拟取代可以增强ALS突变的影响，突出翻译后修饰和ALS连锁突变之间的相互作用。这些结果表明，ALS连锁突变可导致TLS的核功能丧失，这取决于核定位受损的程度。
TLS (translocated in liposarcoma), also known as FUS (fused in sarcoma), is an RNA/DNA-binding protein that plays regulatory roles in transcription, pre-mRNA splicing and mRNA transport. Mutations in TLS are responsible for familial amyotrophic lateral sclerosis (ALS) type 6. Furthermore, TLS-containing intracellular inclusions are found in polyglutamine diseases, sporadic ALS, non-SOD1 familial ALS and a subset of frontotemporal lobar degeneration, indicating a pathological significance of TLS in a wide variety of neurodegenerative diseases. Here, we identified TLS domains that determine intracellular localization of the murine TLS. Among them, PY-NLS located in the C-terminus is a strong determinant of intracellular localization as well as splicing regulation of an E1A-derived minigene. Disruption of PY-NLS promoted the formation of cytoplasmic granules that were partially overlapped with stress granules and P-bodies. Some of the ALS-linked mutations altered both intracellular localization and splicing regulation of TLS, while most mutations alone did not affect splicing regulation. However, phospho-mimetic substitution of Ser505 (or Ser513 in human) could enhance the effects of ALS mutations, highlighting interplay between post-translational modification and ALS-linked mutations. These results demonstrate that ALS-linked mutations can variably cause loss of nuclear functions of TLS depending on the degree of impairment in nuclear localization.
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影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
--
作者：
Andersson MK;Ståhlberg A;Arvidsson Y;Olofsson A;Semb H;Stenman G;Nilsson O;Aman P
通讯作者：
Aman P
影响因子：
16.2
作者：
Kanai, Y;Dohmae, N;Hirokawa, N
通讯作者：
Hirokawa, N
影响因子：
4.8
作者：
Doi, Hiroshi;Okamura, Kazumasa;Nukina, Nobuyuki
通讯作者：
Nukina, Nobuyuki
影响因子：
16.8
作者：
Cansizoglu, Ahmet E.;Lee, Brittany J.;Chook, Yuh Min
通讯作者：
Chook, Yuh Min