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

• Published in: Nature (London) 2015-06, Vol.522 (7556), p.363-367
• Main Authors: Berkovits, Binyamin D., Mayr, Christine
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; 631/80/2023; Amino acids; Binding sites; CD47 Antigen - genetics; CD47 Antigen - metabolism; Cell adhesion & migration; Cell Line; Cell Membrane - metabolism; DNA-Binding Proteins; ELAV Proteins - metabolism; ELAV-Like Protein 1; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Genes; Genes, Reporter; Histone Chaperones - metabolism; Humanities and Social Sciences; Humans; letter; Membrane proteins; Membrane Proteins - metabolism; Membranes; multidisciplinary; Physiological aspects; Polyadenylation; Protein research; Protein Transport; Proteins; rac1 GTP-Binding Protein - metabolism; RNA Isoforms - genetics; RNA Isoforms - metabolism; RNA, Messenger - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Transcription (Genetics); Transcription Factors - metabolism; Translocation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14321

Many human genes undergo alternative cleavage and polyadenylation to generate messenger RNA transcripts with different lengths at the 3' untranslated regions (3' UTRs) but that encode the same protein; now it is shown that these alternative 3' UTRs regulate protein localization. Protein destination depends on 3′ UTR lengths Many human genes undergo an alternative cleavage and polyadenylation process to generate messenger RNA transcripts that have different lengths at the 3′ untranslated regions (3′ UTRs), but still produce the same protein. Binyamin Berkovits and Christine Mayr demonstrate a reason for such differential mRNA processing — alternative 3′ UTRs regulate cellular localization and function of their corresponding proteins. Taking the membrane protein CD47 — which protects cells from phagocytosis — as a model, the authors find that those molecules with long 3′ UTRs are destined to go to the cell surface, while the shorter alternatives localize to the endoplasmic reticulum. 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 1 , 2 , 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 (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 6 , 7 , 8 , 9 , and we show that the long 3′ UTRs of CD44 , ITGA1 and TNF