Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5'TOP mRNAs.

Abstract

A central mechanism of mTOR complex 1 (mTORC1) signaling is the coordinated translation of ribosomal protein and translation factor mRNAs mediated by the 5'-terminal oligopyrimidine motif (5'TOP). Recently, La-related protein 1 (LARP1) was proposed to be the specific regulator of 5'TOP mRNA translation downstream of mTORC1, while eIF4E-binding proteins (4EBP1/2) were suggested to have a general role in translational repression of all transcripts. Here, we use single-molecule translation site imaging of 5'TOP and canonical mRNAs to study the translation of single mRNAs in living cells. Our data reveal that 4EBP1/2 has a dominant role in repression of translation of both 5'TOP and canonical mRNAs during pharmacological inhibition of mTOR. In contrast, we find that LARP1 selectively protects 5'TOP mRNAs from degradation in a transcriptome-wide analysis of mRNA half-lives. Our results clarify the roles of 4EBP1/2 and LARP1 in regulating 5'TOP mRNAs and provide a framework to further study how these factors control cell growth during development and disease.