Functional regulation of tristetraprolin through protein phosphorylation and protein-protein interaction
Date Issued
2016
Date
2016
Author(s)
Yu, Ya-Han
Abstract
Tristetraprolin (TTP) is an RNA-binding protein that mediates the degradation of AU-rich element containing mRNA. The function of TTP is tightly regulated by its protein phosphorylation status and protein-protein interaction. TTP-mediated mRNA decay is through the recruitment of CCR4-NOT deadenylase complex, which consists two deadenylases Cnot6 and Cnot7. Our result reveal that both enzymes of Cnot7 and Cnot6 are required for in vitro deadenylation. In addition to extensively studied p38 pathway, previous reports showed that ERK signaling also can regulate the protein stability, subcellular localization, and function of TTP. By mass spectrometry analysis Ser-316 of TTP was identified to be phosphorylated in response to ERK signaling. Ser-316 phosphorylation of TTP would decrease its interaction with the CCR4-NOT deadenylase complex. Next, we aim to investigate the functional effect of Ser-316 phosphorylation under the physiological condition. We demonstrates that ERK signals induce TTP expression and phosphorylation, which result in changing the binding protein of TTP in LPS-stimulated RAW264.7 and inhibiting 3T3-L1 adipogenesis. Additionally, we observed that Ser-316 phosphorylation can affect the subcellular localization of TTP. On the other hand, transcription co-repressor HDAC3 was identified as TTP-associated proteins in the mass spectrometry analysis. Both of TTP and HDAC3 have been known can negatively regulate NF-κB signaling-mediated transcriptional activation. We demonstrate possible molecular mechanism including that TTP deletion mutants has Transcriptional activity; TTP increases Hdac3 protein stability; and p38-mediated TTP phosphorylation affects its subcellular localization. Collectively, our results might provide evidence to demonstrate the molecular mechanism of TTP phosphorylation and protein-protein interaction on gene regulation.
Subjects
Tristetraprolin
Phosphorylation
ERK signaling
NF-κB signaling
Type
thesis
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