TY - JOUR
T1 - P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
AU - Qi, Mei Yan
AU - Song, Jing Wen
AU - Zhang, Zhuo
AU - Huang, Shuang
AU - Jing, Qing
AU - Matera, A. Gregory
N1 - Funding Information:
We are grateful to Parker Roy (University of Colorado Boulder) for kindly providing ARE-mRNA localization plasmids and Jens Lykke-Andersen (University of California, San Diego) for kindly providing anti-Dcp1a antibody, Myc-RCK, β-GM-CSF, and pTet-TTA plasmid. We thank Chen Wang for critically reading the manuscript. We thank all members of the Jing laboratory for helpful discussions and comments on the manuscript. This work was supported in part by the National Key Research & Development Program of China (2017YFA0103700), the Strategic Priority Research Program of the Chinese Academy of Science (XDA16020903), and the National Natural Science Foundation of China (91739301, 31229002, 81301855, and 91339205).
Publisher Copyright:
© 2018 Qi, Song, et al.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - 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.
AB - 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.
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U2 - 10.1091/mbc.E17-02-0105
DO - 10.1091/mbc.E17-02-0105
M3 - Article
AN - SCOPUS:85046434789
SN - 1059-1524
VL - 29
SP - 988
EP - 1002
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 8
ER -