AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation

Abstract

In the present study, we investigated the 3′ untranslated region (UTR) of the mouse core clock gene cryptochrome 1 ( Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3′UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3′UTR is widely known to function as a cis-acting element of mRNA degradation. The 3′UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3′UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3′UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3′UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3′UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3′UTR facilitates interaction with the 5′ end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA.