Alternative 3' UTRs act as scaffolds to regulate membrane protein localization.
Alternative 3' UTRs act as scaffolds to regulate membrane protein localization.
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DOI：
10.1038/nature14321
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发表时间：
2015-06-18
期刊：
影响因子：
64.8
通讯作者：
Mayr C
中科院分区：
文献类型：
--
作者：
Berkovits BD;Mayr C
大约一半的人类基因使用交替切割和多聚腺苷酸化（阿帕）来产生mRNA转录物，其3'非翻译区（3'UTR）的长度不同，同时产生相同的蛋白质。在这里，我们显示在人类细胞系中，替代3'UTR差异调节膜蛋白的定位。CD47的长3'UTR使得CD47蛋白能够有效地在细胞表面表达，而短3'UTR主要将CD47蛋白定位于内质网。CD47蛋白定位发生在免疫后且独立于RNA定位。在我们的3'UTR依赖性蛋白定位模型中，CD47的长3'UTR充当支架以将含有RNA结合蛋白HuR（也称为ELAVL1）和SET的蛋白复合物募集到翻译位点。这促进SET与CD47的新翻译的胞质结构域的相互作用，并导致随后CD47通过活化的RAC 1易位至质膜。我们还表明，CD47蛋白具有不同的功能，这取决于它是由短或长的3'UTR亚型产生的。因此，阿帕有助于蛋白质组的功能多样性而不改变氨基酸序列。3'UTR依赖性蛋白定位有可能成为膜蛋白的广泛运输机制，因为HuR结合数千种mRNA，并且我们表明，与相应的短3' UTR相比，由HuR结合的CD44、ITGA 1和TNFRSF13 C的长3'UTR增加表面蛋白表达。我们认为，在翻译过程中，3'UTR的支架功能促进蛋白质与新生蛋白质的结合，以指导它们的运输或功能，并且3' UTR的这种作用可以由阿帕调节。
About half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the length of their 3' untranslated regions (3'UTRs) while producing the same protein . Here we show in human cell lines that alternative 3' UTRs differentially regulate the localization of membrane proteins. The long 3'UTR of CD47 enables efficient cell surface expression of CD47 protein, whereas the short 3'UTR primarily localizes CD47 protein to the endoplasmic reticulum. CD47 protein localization occurs post-translationally and independently of RNA localization. In our model of 3' UTR-dependent protein localization, the long 3' UTR of CD47 acts as a scaffold to recruit a protein complex containing the RNA-binding protein HuR (also known as ELAVL1) and SET to the site of translation. This facilitates interaction of SET with the newly translated cytoplasmic domains of CD47 and results in subsequent translocation of CD47 to the plasma membrane via activated RAC1 . We also show that CD47 protein has different functions depending on whether it was generated by the short or long 3'UTR isoforms. Thus, ApA contributes to the functional diversity of the proteome without changing the amino acid sequence. 3' UTR-dependent protein localization has the potential to be a widespread trafficking mechanism for membrane proteins because HuR binds to thousands of mRNAs, and we show that the long 3' UTRs of CD44, ITGA1 and TNFRSF13C, which are bound by HuR, increase surface protein expression compared to their corresponding short 3' UTRs. We propose that during translation the scaffold function of 3' UTRs facilitates binding of proteins to nascent proteins to direct their transport or function—and that this role of 3' UTRs can be regulated by ApA.