mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading

Translation of 5′ terminal oligopyrimidine (TOP) mRNAs encoding the protein synthesis machinery is strictly regulated by an amino-acid-sensing mTOR pathway. However, its regulatory mechanism remains elusive. Here, we demonstrate that TOP mRNA translation positively correlates with its poly(A) tail length under mTOR active/amino-acid-rich conditions, suggesting that TOP mRNAs are post-transcriptionally controlled by poly(A) tail-length regulation. Consistent with this, the tail length of TOP mRNAs dynamically fluctuates in response to amino acid availability. The poly(A) tail shortens under mTOR active/amino-acid-rich conditions, whereas the long-tailed TOP mRNAs accumulate under mTOR inactive/amino-acid-starved (AAS) conditions. An RNA-binding protein, LARP1, is indispensable for the process. LARP1 interacts with non-canonical poly(A) polymerases and induces post-transcriptional polyadenylation of the target. Our findings illustrate that LARP1 contributes to the selective accumulation of TOP mRNAs with long poly(A) tails under AAS, resulting in accelerated ribosomal loading onto TOP mRNAs for the resumption of translation after AAS. [Display omitted] •TOP mRNA poly(A) tail length positively correlates with ribosome loading onto mRNA•TOP mRNA poly(A) tail length dynamically fluctuates in response to mTOR activity•LARP1 preserves long-poly(A)-tailed TOP mRNAs under chronic mTOR inactivation•LARP1 binds poly(A) polymerases to induce polyadenylation of target mRNAs TOP genes encode protein synthesis machineries, and their expression levels have an impact on the cellular translation system. Ogami et al. show that LARP1 preserves long polyadenylated forms of TOP mRNAs under chronic mTOR inactivation to facilitate the rapid resumption of translation when mTOR is reactivated.