Mitra Mithun, Johnson Elizabeth L, Coller Hilary A
Department of Molecular, Cell and Developmental Biology, UCLA, and Department of Biological Chemistry, David Geffen School of Medicine, Los Angeles, CA 90095.
Department of Microbiology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Trends Cell Mol Biol. 2015;10:37-47.
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.
对于许多基因组位点而言，存在多个潜在的切割和聚腺苷酸化位点，从而导致产生多种不同的转录本。当近端聚腺苷酸化位点位于转录本的编码区域内时，可变聚腺苷酸化可导致产生具有不同氨基酸序列和潜在不同功能的蛋白质。在大多数情况下，不同的可能聚腺苷酸化位点都存在于3'非翻译区（UTR）内，并且编码蛋白质的氨基酸序列不受聚腺苷酸化位点选择的影响。在个别情况下，3'UTR中近端与远端聚腺苷酸化位点的选择可显著影响转录本的稳定性和可翻译性。在某些情况下，UTR可变聚腺苷酸化产生具有不同亚细胞定位模式的RNA异构体，并且可以以RNA引导的方式调节编码蛋白质的定位。在最近的一篇论文中，克里斯汀·迈尔（Christine Mayr）的实验室证明，跨膜蛋白CD47的可变聚腺苷酸化导致转录本具有相同的定位模式，但当它由使用3'UTR中近端聚腺苷酸化位点产生的转录本编码时，编码的蛋白质定位于内质网，而当转录本由同样在3'UTR中的远端聚腺苷酸化位点编码时，相同的蛋白质定位于质膜。与先前的研究不同，定位机制不依赖于mRNA的差异运输，而是基于RNA介导的蛋白质募集到CD47的细胞质侧，以支持其质膜定位。发现其他跨膜蛋白也受到类似的调节。结果表明，即使蛋白质序列不受影响，聚腺苷酸化位点的选择也会影响蛋白质的定位和功能。此外，编码蛋白质的转录本可以作为支架来募集影响蛋白质命运的其他蛋白质。
