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      Diversion of stress granules and P-bodies during viral infection

      review-article
      , *
      Virology
      Elsevier Inc.
      Stress granules, P-bodies, RNA granules, Translation control

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          Abstract

          RNA granules are structures within cells that impart key regulatory measures on gene expression. Two general types of RNA granules are conserved from yeast to mammals: stress granules (SGs), which contain many translation initiation factors, and processing bodies (P-bodies, PBs), which are enriched for proteins involved in RNA turnover. Because of the inverse relationship between appearance of RNA granules and persistence of translation, many viruses must subvert RNA granule function for replicative purposes. Here we discuss the viruses and mechanisms that manipulate stress granules and P-bodies to promote synthesis of viral proteins. Several themes have emerged for manipulation of RNA granules by viruses: (1) disruption of RNA granules at the mid-phase of infection, (2) prevention of RNA granule assembly throughout infection and (3) co-opting of RNA granule proteins for new or parallel roles in viral reproduction. Viruses must employ one or multiple of these routes for a robust and productive infection to occur. The possible role for RNA granules in promoting innate immune responses poses an additional reason why viruses must counteract the effects of RNA granules for efficient replication.

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          Most cited references81

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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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            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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              Processing bodies require RNA for assembly and contain nontranslating mRNAs.

              Recent experiments have defined cytoplasmic foci, referred to as processing bodies (P-bodies), wherein mRNA decay factors are concentrated and where mRNA decay can occur. However, the physical nature of P-bodies, their relationship to translation, and possible roles of P-bodies in cellular responses remain unclear. We describe four properties of yeast P-bodies that indicate that P-bodies are dynamic structures that contain nontranslating mRNAs and function during cellular responses to stress. First, in vivo and in vitro analysis indicates that P-bodies are dependent on RNA for their formation. Second, the number and size of P-bodies vary in response to glucose deprivation, osmotic stress, exposure to ultraviolet light, and the stage of cell growth. Third, P-bodies vary with the status of the cellular translation machinery. Inhibition of translation initiation by mutations, or cellular stress, results in increased P-bodies. In contrast, inhibition of translation elongation, thereby trapping the mRNA in polysomes, leads to dissociation of P-bodies. Fourth, multiple translation factors and ribosomal proteins are lacking from P-bodies. These results suggest additional biological roles of P-bodies in addition to being sites of mRNA degradation.
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                Author and article information

                Contributors
                Journal
                Virology
                Virology
                Virology
                Elsevier Inc.
                0042-6822
                1096-0341
                2 January 2013
                20 February 2013
                2 January 2013
                : 436
                : 2
                : 255-267
                Affiliations
                Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77035, USA
                Author notes
                [* ]Corresponding author. rlloyd@ 123456bcm.edu
                Article
                S0042-6822(12)00590-9
                10.1016/j.virol.2012.11.017
                3611887
                23290869
                c090a078-ded9-436a-b141-e5a7b442872a
                Copyright © 2012 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 22 October 2012
                : 5 November 2012
                : 28 November 2012
                Categories
                Article

                Microbiology & Virology
                stress granules,p-bodies,rna granules,translation control
                Microbiology & Virology
                stress granules, p-bodies, rna granules, translation control

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