SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export.
SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export.
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DOI：
10.1101/gad.276477.115
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发表时间：
2016-03-01
影响因子：
10.5
通讯作者：
Neugebauer KM
中科院分区：
文献类型：
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作者：
Müller-McNicoll M;Botti V;de Jesus Domingues AM;Brandl H;Schwich OD;Steiner MC;Curk T;Poser I;Zarnack K;Neugebauer KM
在这项研究中，Müller-McNicoll 等人。研究输出机器如何在 mRNA 上组装以及在从细胞核输出 mRNA 之前如何感知 mRNA 成熟度。他们表明，SR 蛋白通过将选择性剪接和 3' 末端形成与体内 mRNA 输出连接起来，充当 NXF1 接头，并提出 SR 蛋白和 NXF1 在 mRNA 上形成三元复合物，特别是在最后的外显子中，并一起穿梭到细胞质。核输出因子 1 (NXF1) 在被特定接头蛋白招募到 mRNA 后将 mRNA 输出到细胞质。人们对细胞如何以及为何使用多种不同的输出接头知之甚少。在这里，我们严格评估 SR 蛋白家族 (SRSF1-7) 的成员作为 NXF1 接头的潜力，将前 mRNA 加工与 mRNA 输出耦合。与该提议一致，超过 1000 个内源 mRNA 需要单独的 SR 蛋白进行体内核输出。为了解决这一机制，通过个体核苷酸分辨率的 UV 交联和免疫沉淀 (iCLIP) 并行确定了 NXF1 和 SRSF1-7 的转录组范围的 RNA 结合谱。 RNA 结合位点的定量比较表明，NXF1 和 SR 蛋白在相邻位点结合 mRNA 靶标，表明存在共结合。 SRSF3 成为最有效的 NXF1 接头，赋予最后外显子中 NXF1 与 RNA 结合的序列特异性。有趣的是，SRSF3 和 SRSF7 显示结合最后外显子中的不同位点，并以相反的方式调节 3' 非翻译区长度。 SRSF3 和 SRSF7 均促进 NXF1 募集至 mRNA。因此，SRSF3 和 SRSF7 将选择性剪接和多聚腺苷酸化与 NXF1 介导的 mRNA 输出结合起来，从而控制具有选择性 3' 末端的转录物的细胞质丰度。
In this study, Müller-McNicoll et al. investigate how export machinery assembles on mRNA and how it senses mRNA maturity before exporting mRNAs from the nucleus. They show that SR proteins act as NXF1 adaptors by connecting alternative splicing and 3′ end formation to mRNA export in vivo and propose that SR proteins and NXF1 form a ternary complex on mRNAs, particularly in last exons, and shuttle together to the cytoplasm. Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1–7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1–7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3′ untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3′ ends.