Tristetraprolin controls the stability of cIAP2 mRNA through binding to the 3'UTR of cIAP2 mRNA

Abstract

cIAP2 is a key regulator of programmed cell death and the NF-κB pathway. Here, we investigated the post-transcriptional regulation of cIAP2 expression by tristetraprolin (TTP). Our results showed that overexpression of TTP reduced the stability of cIAP2 mRNA and the expression level of cIAP2. In addition, TTP destabilized a luciferase mRNA containing cIAP2 mRNA 3'UTR. cIAP2 mRNA 3'UTR contains four AU-rich elements (AREs) and the 2nd ARE was responsible for the TTP-mediated destabilization of the cIAP2 mRNA. RNA EMSA revealed that TTP directly bound to 42 nucleotides from the 3'UTR of cIAP2 mRNA containing the 2nd ARE. However, the 42 nucleotides did not promote TTP-dependent destabilization of mRNA and did not recruit the decapping enzyme Dcp2 and the 5'-3' exonuclease Xrn1. When we used a 52 nucleotide sequence containing an additional 5 nucleotides from cIAP2 mRNA 3'UTR at both ends, this long nucleotide sequences recruited Dcp2 and Xrn1 and promoted TTP-dependent destabilization of mRNA. Collectively, our results suggest that TTP can bind to the 2nd ARE of cIAP2 mRNA 3'UTR and destabilize cIAP2 mRNA by forming complexes with Dcp2 and Xrn1. However, while a short nucleotide sequence containing the 2nd ARE of cIAP2 mRNA can recruit the TTP binding, this cannot recruit Dcp2 and Xrn1 and cannot induce TTP-mediated destabilize the mRNA. Instead, additional nucleotide sequences are required to recruit Dcp2 and Xrn1 and to destabilize mRNA.