Berkovits Binyamin D, Mayr Christine
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York 10065, USA.
Nature. 2015 Jun 18;522(7556):363-7. doi: 10.1038/nature14321. Epub 2015 Apr 20.
About half of human genes use alternative cleavage and polyadenylation (ApA) to generate messenger RNA 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 (ref. 5). 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 this role of 3' UTRs can be regulated by ApA.
约一半的人类基因利用可变切割和多聚腺苷酸化（ApA）来生成信使核糖核酸转录本，这些转录本在3'非翻译区（3'UTR）的长度上存在差异，却能产生相同的蛋白质。我们在人类细胞系中发现，可变3'UTR对膜蛋白的定位具有不同的调节作用。CD47的长3'UTR能使CD47蛋白高效表达于细胞表面，而短3'UTR则主要将CD47蛋白定位在内质网。CD47蛋白的定位发生在翻译后，且与RNA定位无关。在我们的3'UTR依赖性蛋白定位模型中，CD47的长3'UTR作为支架，招募一个包含RNA结合蛋白HuR（也称为ELAVL1）和SET的蛋白复合物至翻译位点。这有助于SET与新翻译的CD47胞质结构域相互作用，并通过激活的RAC1（参考文献5）导致CD47随后转运至质膜。我们还表明，根据其是由短还是长3'UTR异构体产生，CD47蛋白具有不同的功能。因此，ApA在不改变氨基酸序列的情况下，促成了蛋白质组的功能多样性。3'UTR依赖性蛋白定位有可能成为膜蛋白广泛的运输机制，因为HuR能与数千种信使核糖核酸结合，并且我们发现，与相应的短3'UTR相比，HuR结合的CD44、ITGA1和TNFRSF13C的长3'UTR能增加表面蛋白表达。我们提出，在翻译过程中，3'UTR的支架功能有助于蛋白质与新生蛋白结合，以指导其运输或功能——而3'UTR的这一作用可由ApA调节。
