The Renpenning syndrome?associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin?2 receptor
The Renpenning syndrome?associated protein PQBP1 facilitates the nuclear import of splicing factor TXNL4A through the karyopherin?2 receptor
复制标题
Renpenning综合征相关蛋白PQBP1通过核转运蛋白β2受体促进剪接因子TXNL4A向核输入
DOI：
10.1074/jbc.ra119.012214
复制
发表时间：
2020-03-27
影响因子：
4.8
通讯作者：
Zhang, Zi Chao
中科院分区：
文献类型：
--
作者：
Liu, Xian;Dou, Lin-Xia;Zhang, Zi Chao
伦彭宁综合征属于一组X连锁智力障碍疾病。与伦彭宁综合征相关的蛋白质PQBP1（多聚谷氨酰胺结合蛋白1）本质上是无序的，与几种剪接因子相关联，并参与前体mRNA剪接。PQBP1利用其C末端的YxxPxxVL基序与剪接因子TXNL4A（硫氧还蛋白样4A）结合，但这种相互作用的生物学功能尚未阐明。在本研究中，通过在HeLa细胞中进行重组蛋白表达、体外结合实验和免疫荧光显微镜检查，我们发现最近报道的一种与X连锁智力障碍相关的错义突变，导致PQBP1 - P244L变体，破坏了与TXNL4A的相互作用。我们进一步表明这种相互作用对TXNL4A的亚细胞定位至关重要。结合其他缺乏被核输入受体核转运蛋白β2识别所需的功能性核定位信号的PQBP1变体，我们证明PQBP1通过一种搭载机制促进TXNL4A的核输入。这些发现拓展了我们对PQBP1 - TXNL4A相互作用的分子基础以及伦彭宁综合征和相关疾病的病因学和发病机制的理解。
Renpenning syndrome belongs to a group of X-linked intellectual disability disorders. The Renpenning syndrome?associated protein PQBP1 (polyglutamine-binding protein 1) is intrinsically disordered, associates with several splicing factors, and is involved in pre-mRNA splicing. PQBP1 uses its C-terminal YxxPxxVL motif for binding to the splicing factor TXNL4A (thioredoxin like 4A), but the biological function of this interaction has yet to be elucidated. In this study, using recombinant protein expression, in vitro binding assays, and immunofluorescence microscopy in HeLa cells, we found that a recently reported X-linked intellectual disability?associated missense mutation, resulting in the PQBP1-P244L variant, disrupts the interaction with TXNL4A. We further show that this interaction is critical for the subcellular location of TXNL4A. In combination with other PQBP1 variants lacking a functional nuclear localization signal required for recognition by the nuclear import receptor karyopherin ?2, we demonstrate that PQBP1 facilitates the nuclear import of TXNL4A via a piggyback mechanism. These findings expand our understanding of the molecular basis of the PQBP1?TXNL4A interaction and of the etiology and pathogenesis of Renpenning syndrome and related disorders.