Abstract
The destabilization of AU-rich element (ARE)-containing mRNAs mediated by proteins of the TIS11 family is conserved among eukaryotes including Drosophila. Previous studies have demonstrated that Tristetraprolin, a human protein of the TIS11 family, induces the degradation of ARE-containing mRNAs through a large variety of mechanisms including deadenylation, decapping, and P-body targeting. We have previously shown that the degradation of the mRNA encoding the antimicrobial peptide Cecropin A1 (CecA1) is controlled by the TIS11 protein (dTIS11) in Drosophila cells. In this study, we used CecA1 mRNA as a model to investigate the molecular mechanism of dTIS11-mediated mRNA decay. We observed that during the biphasic deadenylation and decay process of this mRNA, dTIS11 enhances deadenylation performed by the CCR4-CAF-NOT complex while the mRNA is still associated with ribosomes. Sequencing of mRNA degradation intermediates revealed that the complete deadenylation of the mRNA triggers its decapping and decay in both the 5'-3' and the 3'-5' directions. Contrary to the observations made for its mammalian homologs, overexpression of dTIS11 does not promote the localization of ARE-containing mRNAs in P-bodies but rather decreases the accumulation of CecA1 mRNA in these structures by enhancing the degradation process. Therefore, our results suggest that proteins of the TIS11 family may have acquired additional functions in the course of evolution from invertebrates to mammals.
Highlights
TIS11 proteins control the degradation of mRNA containing AU-rich elements (ARE)
The destabilization of AU-rich element (ARE)-containing mRNAs mediated by proteins of the TIS11 family is conserved among eukaryotes including Drosophila
Our RNAi experiments indicated that both dTIS11 and CAF1 were necessary for the second phase of deadenylation, whereas depletion of these proteins alone had no detectable influence on the first phase of deadenylation [23]
Summary
TIS11 proteins control the degradation of mRNA containing AU-rich elements (ARE). Results: Drosophila dTIS11 activates the polysomal deadenylation of the ARE mRNA Cecropin A1. In mammalian cells, the observation that both ARE mRNAs and TTP proteins accumulate in P-bodies when the 5Ј-3Ј degradation pathway is inhibited suggested that this mode of degradation is favored in TTP-mediated ARE mRNA decay [18, 19] These observations indicate that in mammals, TTP and the other members of the TIS11 family are multipotent proteins, which favor AMD by enhancing several crucial steps in the mRNA degradation process. Our results suggest that the activity of dTIS11 is mainly based on its capacity to enhance deadenylation in Drosophila cells and that proteins of this family may have acquired additional functions later in the course of evolution from invertebrates to mammals
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