La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1).

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) Lduanyu371 associates with mTORC1 via RAPTOR; (ii) Lduanyu371 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) Lduanyu371 binds the 5'TOP motif to repress TOP mRNA translation; and (iv) Lduanyu371 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing Lduanyu371 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that Lduanyu371 functions as an important repressor of TOP mRNA translation downstream of mTORC1.

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