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

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 AR...

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Autores principales: Qi, Mei-Yan, Song, Jing-Wen, Zhang, Zhuo, Huang, Shuang, Jing, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896936/
https://www.ncbi.nlm.nih.gov/pubmed/29444957
http://dx.doi.org/10.1091/mbc.E17-02-0105
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author Qi, Mei-Yan
Song, Jing-Wen
Zhang, Zhuo
Huang, Shuang
Jing, Qing
author_facet Qi, Mei-Yan
Song, Jing-Wen
Zhang, Zhuo
Huang, Shuang
Jing, Qing
author_sort Qi, Mei-Yan
collection PubMed
description 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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spelling pubmed-58969362018-06-30 P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization Qi, Mei-Yan Song, Jing-Wen Zhang, Zhuo Huang, Shuang Jing, Qing Mol Biol Cell Articles 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. The American Society for Cell Biology 2018-04-15 /pmc/articles/PMC5896936/ /pubmed/29444957 http://dx.doi.org/10.1091/mbc.E17-02-0105 Text en © 2018 Qi, Song, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0/ This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Qi, Mei-Yan
Song, Jing-Wen
Zhang, Zhuo
Huang, Shuang
Jing, Qing
P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
title P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
title_full P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
title_fullStr P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
title_full_unstemmed P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
title_short P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization
title_sort p38 activation induces the dissociation of tristetraprolin from argonaute 2 to increase are-mrna stabilization
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896936/
https://www.ncbi.nlm.nih.gov/pubmed/29444957
http://dx.doi.org/10.1091/mbc.E17-02-0105
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