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.
Bibliographical noteFunding Information:
We thank Dr Kwiatkowski at Bringham and Women’s Hospital and Harvard Medical School for providing us TSC1+/+ and TSC1−/− MEF cell lines and HCV29 bladder cancer cell lines used in this study. We also thank Mr Todd Markowski and Dr LeeAnn Higgins at the Center for Mass Spectrometry and Proteomics, University of Minnesota, for their work in peptide fractionation and LC–MS/MS analysis. This work was supported in part by the following funding: Institutional Research Grant (118198-IRG-58-001-52-IRG76) from the American Cancer Society for J.Y., and the grant for the Bio & Medical Technology Development Program (2012M3A9B4028738) by the National Research Foundation of Korea (NRF) for K.-S.K and J.Y., NSF III 117153 for R.K. and GM097057, AG039758, ADA 7-12-BS-093 and W81XWH-13-1-0060 for D.-H.K.