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      Regulation of stress granules and P‐bodies during RNA virus infection

      review-article
      1 ,
      Wiley Interdisciplinary Reviews. RNA
      John Wiley & Sons, Inc.

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          Abstract

          RNA granules are structures within cells that play major roles in gene expression and homeostasis. Two principle kinds of RNA granules are conserved from yeast to mammals: stress granules (SGs), which contain stalled translation initiation complexes, and processing bodies (P‐bodies, PBs), which are enriched with factors involved in RNA turnover. Since RNA granules are associated with silenced transcripts, viruses subvert RNA granule function for replicative advantages. This review, focusing on RNA viruses, discusses mechanisms that manipulate stress granules and P‐bodies to promote synthesis of viral proteins. Three main themes have emerged for how viruses manipulate RNA granules; (1) cleavage of key host factors, (2) control of protein kinase R (PKR) activation, and (3) redirecting RNA granule components for new or parallel roles in viral reproduction, at the same time disrupting RNA granules. Viruses utilize one or more of these routes to achieve robust and productive infection. WIREs RNA 2013, 4:317–331. doi: 10.1002/wrna.1162

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            RNA in Disease and Development > RNA in Disease

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          Stress granules: the Tao of RNA triage.

          Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay.
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            Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies.

            Cellular granules lacking boundary membranes harbor RNAs and their associated proteins and play diverse roles controlling the timing and location of protein synthesis. Formation of such granules was emulated by treatment of mouse brain extracts and human cell lysates with a biotinylated isoxazole (b-isox) chemical. Deep sequencing of the associated RNAs revealed an enrichment for mRNAs known to be recruited to neuronal granules used for dendritic transport and localized translation at synapses. Precipitated mRNAs contain extended 3' UTR sequences and an enrichment in binding sites for known granule-associated proteins. Hydrogels composed of the low complexity (LC) sequence domain of FUS recruited and retained the same mRNAs as were selectively precipitated by the b-isox chemical. Phosphorylation of the LC domain of FUS prevented hydrogel retention, offering a conceptual means of dynamic, signal-dependent control of RNA granule assembly. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Novel role of PKR in inflammasome activation and HMGB1 release

              The inflammasome regulates release of caspase activation-dependent cytokines, including IL-1β, IL-18, and high-mobility group box 1 (HMGB1) 1-5 . During the course of studying HMGB1 release mechanisms, we discovered an important role of double-stranded RNA dependent protein kinase (PKR) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. Typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3), NLR family pyrin domain-containing 1 (NLRP1), NLR family CARD domain-containing protein 4 (NLRC4), Absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell free system with recombinant NLRP3, ASC and pro-casapse-1 reconstitutes inflammasome activity. These results reveal a critical role of PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
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                Author and article information

                Contributors
                rlloyd@bcm.edu
                Journal
                Wiley Interdiscip Rev RNA
                Wiley Interdiscip Rev RNA
                10.1002/(ISSN)1757-7012
                WRNA
                Wiley Interdisciplinary Reviews. RNA
                John Wiley & Sons, Inc. (Hoboken, USA )
                1757-7004
                1757-7012
                03 April 2013
                May-Jun 2013
                : 4
                : 3 ( doiID: 10.1002/wrna.v4.3 )
                : 317-331
                Affiliations
                [ 1 ]Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
                Author notes
                [*] [* ]Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
                Article
                WRNA1162
                10.1002/wrna.1162
                3652661
                23554219
                6d71203b-090d-4913-b857-4bbc35d4c0b8
                Copyright © 2013 John Wiley & Sons, Ltd.

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                Page count
                Figures: 3, Tables: 0, References: 110, Pages: 15
                Categories
                RNA in Disease
                Advanced Review
                Advanced Reviews
                Custom metadata
                2.0
                May/June 2013
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

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