Alternative polyadenylation can regulate post-translational membrane localization.

For many genomic loci, there are more than one potential cleavage and polyadenylation site, resulting in the generation of multiple distinct transcripts. When the proximal polyadenylation site is present within the coding region of the transcript, alternative polyadenylation can result in proteins with distinct amino acid sequences and potentially distinct functions. In most cases, the different possible polyadenylation sites are all present within the 3' untranslated regions (UTRs), and the amino acid sequence of the encoded proteins are not affected by polyadenylation site selection. In individual instances, the selection of the proximal versus distal polyadenylation site in the 3'UTR can dramatically affect transcript stability and translatability. In some instances, UTR alternative polyadenylation generates RNA isoforms that have distinct subcellular localization patterns, and that can regulate the location of the encoded protein in an RNA-guided manner. In a recent paper, the laboratory of Christine Mayr demonstrated that alternative polyadenylation of the transmembrane protein CD47 results in transcripts with the same localization pattern, but the encoded protein localizes to the endoplasmic reticulum when it is encoded by the transcript generated by using the proximal polyadenylation site in 3'UTR, and the identical protein localizes to the plasma membrane when the transcript is encoded by the distal polyadenylation site, also in the 3' UTR. Unlike previous studies, the mechanism of localization does not rely on differential trafficking of the mRNA and is instead, based on RNA-mediated recruitment of proteins to the cytoplasmic side of CD47 that support its plasma membrane localization. Other transmembrane proteins were discovered to be regulated similarly. The results demonstrate that the choice of polyadenylation site can affect protein localization and function, even when the sequence of the protein is unaffected. Further, the transcript encoding a protein can serve as a scaffold to recruit additional proteins that affect the protein's fate.