Abstract
Mammalian target of rapamycin (mTOR) enhances translation from a subset of messenger RNAs containing distinct 5'-untranslated region (UTR) sequence features. Here we identify 3'-UTR shortening of mRNAs as an additional molecular signature of mTOR activation and show that 3'-UTR shortening enhances the translation of specific mRNAs. Using genetic or chemical modulations of mTOR activity in cells or mouse tissues, we show that cellular mTOR activity is crucial for 3'-UTR shortening. Although long 3'-UTR-containing transcripts minimally contribute to translation, 3-'UTR-shortened transcripts efficiently form polysomes in the mTOR-activated cells, leading to increased protein production. Strikingly, selected E2 and E3 components of ubiquitin ligase complexes are enriched by this mechanism, resulting in elevated levels of protein ubiquitination on mTOR activation. Together, these findings identify a previously uncharacterized role for mTOR in the selective regulation of protein synthesis by modulating 3'-UTR length of mRNAs.
Highlights
Mammalian target of rapamycin enhances translation from a subset of messenger RNAs containing distinct 50-untranslated region (UTR) sequence features
A precise mechanism(s) of how Mammalian target of rapamycin (mTOR) activation leads to the 30-untranslated region (30-UTR) shortening in selected transcripts is unknown, we found that almost all known 30-end processing factors alter their expression on changes in cellular mTOR activity in TSC1 À / À compared with WT mouse embryonic fibroblast (MEF), suggesting that mTOR-mediated 30-UTR shortening occurs by multiple factors (Supplementary Data 3)
Analysis on pathways enriched in 30-UTR-shortened transcripts and quantitative proteomics on mTOR activation identified ubiquitin-mediated proteolysis as an additional target pathway of mTOR
Summary
Mammalian target of rapamycin (mTOR) enhances translation from a subset of messenger RNAs containing distinct 50-untranslated region (UTR) sequence features. Further sequence analysis revealed that canonical or non-canonical PAS(s) exists around the regions showing the signal drop This indicates that the synthesis of these transcripts terminated early in the 30-most exon using the proximal PASs for polyadenylation, suggesting a predominant production of mRNA isoforms with a shorter 30-UTR in the mTOR-activated transcriptome (Fig. 1a and Supplementary Fig. 1a, yellow box, and Supplementary Data 1). Twelve genes, covering a wide range of P-values, were randomly selected from the 30-UTR shortening data set; all showed the RSI 40 in TSCI À / À (Fig. 1d and see Supplementary Fig. 1d,e for alternative presentations of the data using different experimental and calculation methods), validating our RNA-seq data analysis Together, these data strongly suggest that mTOR activation in cells leads to a preferred usage of proximal PAS in the 30-most exon of mRNAs and results in transcriptome-wide 30-UTR shortening
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