Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype
Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype
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DOI：
10.1126/scisignal.aao1822
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发表时间：
2017-11-21
影响因子：
7.3
通讯作者：
Meran, Soma
中科院分区：
文献类型：
--
作者：
Midgley, Adam C.;Oltean, Sebastian;Meran, Soma
细胞表面蛋白CD 44参与多种生理过程，其异常功能与多种病理学有关，如癌症、免疫失调和纤维化。CD 44生物活性的多样性部分是由通过选择性剪接产生不同的CD 44同种型所赋予的。我们发现了一个意想不到的功能，无处不在的透明质酸降解酶，透明质酸酶2（HYAL 2），作为一个调节CD 44剪接。标准CD 44与纤维化疾病相关，其产生通过富含丝氨酸-精氨酸（SR）蛋白介导的外显子排除来促进。骨形态发生蛋白7可抑制肌成纤维细胞表型，从而刺激HYAL 2核转位。核HYAL 2从剪接体中置换SR蛋白，从而使HYAL 2、剪接体组分（U1和U2小核核糖核蛋白）和CD 44前体mRNA形成复合物。这阻止了双外显子剪接并促进了CD 44外显子11和12的包含，这促进了抗纤维化CD 44亚型CD 44 v7/8在细胞表面的积累。这些数据表明，以前未描述的机制，调节CD 44选择性剪接事件，相关的进行性纤维化的细胞表型的调节。
The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine-rich (SR) protein-mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double-exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis.