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Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice
Nociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3′ end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates tra...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750225/ https://www.ncbi.nlm.nih.gov/pubmed/29295980 http://dx.doi.org/10.1038/s41467-017-02449-5 |
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author | Barragán-Iglesias, Paulino Lou, Tzu-Fang Bhat, Vandita D. Megat, Salim Burton, Michael D. Price, Theodore J. Campbell, Zachary T. |
author_facet | Barragán-Iglesias, Paulino Lou, Tzu-Fang Bhat, Vandita D. Megat, Salim Burton, Michael D. Price, Theodore J. Campbell, Zachary T. |
author_sort | Barragán-Iglesias, Paulino |
collection | PubMed |
description | Nociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3′ end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates translation initiation by bridging the Poly(A) tail to the eukaryotic initiation factor 4F complex associated with the mRNA cap. Here, we use unbiased assessment of PABP binding specificity to generate a chemically modified RNA-based competitive inhibitor of PABP. The resulting RNA mimic, which we designated as the Poly(A) SPOT-ON, is more stable than unmodified RNA and binds PABP with high affinity and selectivity in vitro. We show that injection of the Poly(A) SPOT-ON at the site of an injury can attenuate behavioral response to pain. Collectively, these results suggest that PABP is integral for nociceptive plasticity. The general strategy described here provides a broad new source of mechanism-based inhibitors for RNA-binding proteins and is applicable for in vivo studies. |
format | Online Article Text |
id | pubmed-5750225 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57502252018-01-13 Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice Barragán-Iglesias, Paulino Lou, Tzu-Fang Bhat, Vandita D. Megat, Salim Burton, Michael D. Price, Theodore J. Campbell, Zachary T. Nat Commun Article Nociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3′ end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates translation initiation by bridging the Poly(A) tail to the eukaryotic initiation factor 4F complex associated with the mRNA cap. Here, we use unbiased assessment of PABP binding specificity to generate a chemically modified RNA-based competitive inhibitor of PABP. The resulting RNA mimic, which we designated as the Poly(A) SPOT-ON, is more stable than unmodified RNA and binds PABP with high affinity and selectivity in vitro. We show that injection of the Poly(A) SPOT-ON at the site of an injury can attenuate behavioral response to pain. Collectively, these results suggest that PABP is integral for nociceptive plasticity. The general strategy described here provides a broad new source of mechanism-based inhibitors for RNA-binding proteins and is applicable for in vivo studies. Nature Publishing Group UK 2018-01-02 /pmc/articles/PMC5750225/ /pubmed/29295980 http://dx.doi.org/10.1038/s41467-017-02449-5 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Barragán-Iglesias, Paulino Lou, Tzu-Fang Bhat, Vandita D. Megat, Salim Burton, Michael D. Price, Theodore J. Campbell, Zachary T. Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice |
title | Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice |
title_full | Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice |
title_fullStr | Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice |
title_full_unstemmed | Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice |
title_short | Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice |
title_sort | inhibition of poly(a)-binding protein with a synthetic rna mimic reduces pain sensitization in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750225/ https://www.ncbi.nlm.nih.gov/pubmed/29295980 http://dx.doi.org/10.1038/s41467-017-02449-5 |
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