Alternative 3'UTRs act as scaffolds to regulate membrane protein localization

• Published in: Nature (London) 2015-04, Vol.522 (7556), p.363-367
• Main Authors: Berkovits, Binyamin D., Mayr, Christine
• Format: Article
• Language: English
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14321

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 1 – 3 . 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 4 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 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 6 – 9 , 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.