LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
Sungki Hong,
Mallory A Freeberg,
Ting Han,
Avani Kamath,
Yao Yao,
Tomoko Fukuda,
Tsukasa Suzuki,
John K Kim,
Ken Inoki
Affiliations
Sungki Hong
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Mallory A Freeberg
Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United States
Ting Han
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Avani Kamath
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Yao Yao
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Tomoko Fukuda
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Tsukasa Suzuki
Life Sciences Institute, University of Michigan, Ann Arbor, United States
John K Kim
Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, United States
Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5’ and 3’UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3’UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis.
