Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1.
In human cells, a critical pathway in gene regulation subjects mRNAs with AU-rich elements (AREs) to rapid decay by a poorly understood process. AREs have been shown to directly activate deadenylation, decapping, or 3'-to-5' exonucleolytic decay. We demonstrate that enzymes involved in all three of these mRNA decay processes, as well as 5'-to-3' exonucleolytic decay, associate with the protein tristetraprolin (TTP) and its homolog BRF-1, which bind AREs and activate mRNA decay. TTP and BRF-1 each contain two activation domains that can activate mRNA decay after fusion to a heterologous RNA-binding protein, and inhibit ARE-mediated mRNA decay when overexpressed. Both activation domains employ trans-acting factors to trigger mRNA decay, and the N-terminal activation domain functions as a binding platform for mRNA decay enzymes. Our data suggest that the TTP protein family functions as a molecular link between ARE-containing mRNAs and the mRNA decay machinery by recruitment of mRNA decay enzymes, and help explain how deadenylation, decapping, and exonucleolytic decay can all be independently activated on ARE-containing mRNAs. This describes a potentially regulated step in activation of mRNA decay.
Lykke-Andersen
Jens
J
Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA. Jens.Lykke-Anersen@colorado.edu
Wagner
Eileen
E
D051817:Butyrate Response Factor 1; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism*; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism*; D051816:Tristetraprolin
C441028:BRF1 protein, human; D051817:Butyrate Response Factor 1; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D035381:TATA-Binding Protein Associated Factors; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D004722:Endoribonucleases; D012260:Ribonucleases; C467723:DCP2 protein, human