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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • CD47 Antigen / genetics*
  • CD47 Antigen / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • DNA-Binding Proteins
  • ELAV Proteins / metabolism
  • ELAV-Like Protein 1
  • Endoplasmic Reticulum / metabolism
  • Genes, Reporter
  • Histone Chaperones / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Polyadenylation
  • Protein Transport
  • RNA Isoforms / genetics*
  • RNA Isoforms / metabolism
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • 3' Untranslated Regions
  • CD47 Antigen
  • CD47 protein, human
  • DNA-Binding Proteins
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Histone Chaperones
  • Membrane Proteins
  • RAC1 protein, human
  • RNA Isoforms
  • RNA, Messenger
  • SET protein, human
  • Transcription Factors
  • rac1 GTP-Binding Protein