Angulin proteins are a group of evolutionally conserved type I transmembrane proteins that contain an extracellular Ig-like domain. In mammals, three angulin proteins have been identified, namely immunoglobulin-like domain containing receptor 1 (ILDR1), immunoglobulin-like domain containing receptor 2 (ILDR2), and lipolysis-stimulated lipoprotein receptor (LSR). All three proteins have been shown to localize at tight junctions (TJs) and are important for TJ formation. Mutations in ILDR1 gene have been shown to cause non-syndromic hearing loss (NSHL). In the present work, we show that ILDR1 binds to splicing factors TRA2A, TRA2B, and SRSF1, and translocates into the nuclei when the splicing factors are present. Moreover, ILDR1 affects alternative splicing of Tubulin delta 1 (TUBD1), IQ motif containing B1 (IQCB1), and Protocadherin 19 (Pcdh19). Further investigation show that ILDR2, but not LSR, also binds to the splicing factors and regulates alternative splicing. When endogenous ILDR1 and ILDR2 expression is knockdown with siRNAs in cultured cells, alternative splicing of TUBD1 and IQCB1 is affected. In conclusion, we show here that angulin proteins ILDR1 and ILDR2 are involved in alternative pre-mRNA splicing via binding to splicing factors TRA2A, TRA2B, or SRSF1.

中文翻译：

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Angulin蛋白ILDR1和ILDR2通过与剪接因子TRA2A，TRA2B或SRSF1结合来调节替代的前mRNA剪接。

Angulin蛋白是一组进化保守的I型跨膜蛋白，其中包含细胞外Ig样结构域。在哺乳动物中，已鉴定出三种血管紧张素蛋白，即含有免疫球蛋白样结构域的受体1（ILDR1），含有免疫球蛋白样结构域的受体2（ILDR2）和经脂解刺激的脂蛋白受体（LSR）。已显示所有这三种蛋白质都位于紧密连接（TJ）处，并且对于TJ的形成很重要。ILDR1基因的突变已显示会导致非综合征性听力损失（NSHL）。在目前的工作中，我们表明ILDR1结合剪接因子TRA2A，TRA2B和SRSF1，并在存在剪接因子时易位到核中。此外，ILDR1影响微管蛋白delta 1（TUBD1），含B1的IQ基序（IQCB1）和原钙粘蛋白19（Pcdh19）的可变剪接。进一步的研究表明，ILDR2（而不是LSR）也与剪接因子结合并调节其他剪接。当用培养细胞中的siRNA敲低内源性ILDR1和ILDR2的表达时，TUBD1和IQCB1的可变剪接受到影响。总而言之，我们在这里显示血管生成蛋白ILDR1和ILDR2通过与剪接因子TRA2A，TRA2B或SRSF1结合而参与了替代性的pre-mRNA剪接。