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Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1
Stress granules (SGs) are dynamic cytoplasmic repositories containing translationally silenced mRNAs that assemble upon cellular stress. We recently reported that the SG nucleating protein G3BP1 promotes antiviral activity and is essential in double-stranded RNA-dependent protein kinase (PKR) recrui...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Microbiology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453520/ https://www.ncbi.nlm.nih.gov/pubmed/25784705 http://dx.doi.org/10.1128/mBio.02486-14 |
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author | Reineke, Lucas C. Kedersha, Nancy Langereis, Martijn A. van Kuppeveld, Frank J. M. Lloyd, Richard E. |
author_facet | Reineke, Lucas C. Kedersha, Nancy Langereis, Martijn A. van Kuppeveld, Frank J. M. Lloyd, Richard E. |
author_sort | Reineke, Lucas C. |
collection | PubMed |
description | Stress granules (SGs) are dynamic cytoplasmic repositories containing translationally silenced mRNAs that assemble upon cellular stress. We recently reported that the SG nucleating protein G3BP1 promotes antiviral activity and is essential in double-stranded RNA-dependent protein kinase (PKR) recruitment to stress granules, thereby driving phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Here, we delineate the mechanism for SG-dependent PKR activation. We show that G3BP1 and inactive PKR directly interact with each other, dependent on both the NTF2-like and PXXP domains of G3BP1. The G3BP1-interacting protein Caprin1 also directly interacts with PKR, regulates efficient PKR activation at the stress granule, and is also integral for the release of active PKR into the cytoplasm to engage in substrate recognition. The G3BP1-Caprin1-PKR complex represents a new mode of PKR activation and is important for antiviral activity of G3BP1 and PKR during infection with mengovirus. Our data links stress responses and their resultant SGs with innate immune activation through PKR without a requirement for foreign double-stranded RNA (dsRNA) pattern recognition. |
format | Online Article Text |
id | pubmed-4453520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Society of Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-44535202015-06-03 Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 Reineke, Lucas C. Kedersha, Nancy Langereis, Martijn A. van Kuppeveld, Frank J. M. Lloyd, Richard E. mBio Research Article Stress granules (SGs) are dynamic cytoplasmic repositories containing translationally silenced mRNAs that assemble upon cellular stress. We recently reported that the SG nucleating protein G3BP1 promotes antiviral activity and is essential in double-stranded RNA-dependent protein kinase (PKR) recruitment to stress granules, thereby driving phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Here, we delineate the mechanism for SG-dependent PKR activation. We show that G3BP1 and inactive PKR directly interact with each other, dependent on both the NTF2-like and PXXP domains of G3BP1. The G3BP1-interacting protein Caprin1 also directly interacts with PKR, regulates efficient PKR activation at the stress granule, and is also integral for the release of active PKR into the cytoplasm to engage in substrate recognition. The G3BP1-Caprin1-PKR complex represents a new mode of PKR activation and is important for antiviral activity of G3BP1 and PKR during infection with mengovirus. Our data links stress responses and their resultant SGs with innate immune activation through PKR without a requirement for foreign double-stranded RNA (dsRNA) pattern recognition. American Society of Microbiology 2015-03-17 /pmc/articles/PMC4453520/ /pubmed/25784705 http://dx.doi.org/10.1128/mBio.02486-14 Text en Copyright © 2015 Reineke et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Reineke, Lucas C. Kedersha, Nancy Langereis, Martijn A. van Kuppeveld, Frank J. M. Lloyd, Richard E. Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 |
title | Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 |
title_full | Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 |
title_fullStr | Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 |
title_full_unstemmed | Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 |
title_short | Stress Granules Regulate Double-Stranded RNA-Dependent Protein Kinase Activation through a Complex Containing G3BP1 and Caprin1 |
title_sort | stress granules regulate double-stranded rna-dependent protein kinase activation through a complex containing g3bp1 and caprin1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453520/ https://www.ncbi.nlm.nih.gov/pubmed/25784705 http://dx.doi.org/10.1128/mBio.02486-14 |
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