MRNA 3′-UTR shortening is a molecular signature of mTORC1 activation

Jae Woong Chang; Wei Zhang; Hsin Sung Yeh; Ebbing P. De Jong; Semo Jun; Kwan Hyun Kim; Sun S. Bae; Kenneth Beckman; Tae Hyun Hwang; Kye Seong Kim; Do Hyung Kim; Timothy J. Griffin; Rui Kuang; Jeongsik Yong

doi:10.1038/ncomms8218

MRNA 3′-UTR shortening is a molecular signature of mTORC1 activation

Jae Woong Chang, Wei Zhang, Hsin Sung Yeh, Ebbing P. De Jong, Semo Jun, Kwan Hyun Kim, Sun S. Bae, Kenneth Beckman, Tae Hyun Hwang, Kye Seong Kim, Do Hyung Kim, Timothy J. Griffin, Rui Kuang, Jeongsik Yong

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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.

Original language	English (US)
Article number	7218
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8218
State	Published - Jun 15 2015

Bibliographical note

Funding 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.

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title = "MRNA 3′-UTR shortening is a molecular signature of mTORC1 activation",

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.",

author = "Chang, {Jae Woong} and Wei Zhang and Yeh, {Hsin Sung} and {De Jong}, {Ebbing P.} and Semo Jun and Kim, {Kwan Hyun} and Bae, {Sun S.} and Kenneth Beckman and Hwang, {Tae Hyun} and Kim, {Kye Seong} and Kim, {Do Hyung} and Griffin, {Timothy J.} and Rui Kuang and Jeongsik Yong",

note = "Funding Information: We thank Dr Kwiatkowski at Bringham and Women{\textquoteright}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.",

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AU - Zhang, Wei

AU - Yeh, Hsin Sung

AU - De Jong, Ebbing P.

AU - Jun, Semo

AU - Kim, Kwan Hyun

AU - Bae, Sun S.

AU - Beckman, Kenneth

AU - Hwang, Tae Hyun

AU - Kim, Kye Seong

AU - Kim, Do Hyung

AU - Griffin, Timothy J.

AU - Kuang, Rui

AU - Yong, Jeongsik

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PY - 2015/6/15

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N2 - 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.

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MRNA 3′-UTR shortening is a molecular signature of mTORC1 activation

Abstract

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