P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization

Mei Yan Qi, Jing Wen Song, Zhuo Zhang, Shuang Huang, Qing Jing, A. Gregory Matera

Research output: Contribution to journalArticle

Abstract

Tristetraprolin (TTP) destabilizes AU-rich element (ARE)-containing mRNA by directly binding with their 3′UTR. P38 stimulation substantially increases ARE-mRNA stability, at least through repressing TTP. However, the mechanism by which P38 keeps TTP inactive has not been fully understood. TTP and ARE-mRNA localize to processing bodies (PBs), the mRNA granules associated with mRNA silencing. Here, we detected the influence of P38 on TTP localization within PBs and found that P38 regulates TTP localization within PBs. Through luciferase-based systems, we demonstrated that PBs depletion significantly increased ARE-mRNA stability inhibited by TTP. Additionally, we provided evidence that the microRNA-induced silencing complex (miRISC) core member Ago2 is required for TTP distribution within PBs. Importantly, the cooperation of TTP and Ago2 is a prerequisite for effective ARE-mRNA degradation. Moreover, Dcp1a and Dcp2 act downstream of Ago2 and TTP engaging in ARE-mRNA decay. Finally, we demonstrated that P38 activation represses the interaction between TTP and Ago2 due to TTP phosphorylation, which impairs TTP localization within PBs and ARE-mRNA degradation. Collectively, our study revealed a novel mechanism through which P38 activation repressed the cooperation of TTP with Ago2, thus ensuring that ARE-mRNA does not associate with PBs and remains stable.

Original languageEnglish (US)
Pages (from-to)988-1002
Number of pages15
JournalMolecular Biology of the Cell
Volume29
Issue number8
DOIs
StatePublished - Apr 15 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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