How Do Viruses Interact with Stress-Associated RNA Granules?

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
PLoS Pathogens (Impact Factor: 7.56). 06/2012; 8(6):e1002741. DOI: 10.1371/journal.ppat.1002741
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    • "proteases which include 3C and 2A proteinases have been shown to attenuate the Type I IFN response by cleaving focal adhesion kinase, MDA5, RIG-1, and MAVS host proteins (Bozym et al., 2012; Mukherjee et al., 2011; Feng et al., 2014a). A common feature following any infection of the host cell includes the induction of the stress response which acts against viral infection by inhibiting protein synthesis (Lloyd, 2012). Viral infection can trigger stress granules (SG) which comprise translationally silenced messenger ribonucleoproteins thereby inhibiting the viral genome from being translated (Onomoto et al., 2014; Lloyd, 2013). "
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    ABSTRACT: Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses - although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 10/2015; 484. DOI:10.1016/j.virol.2015.06.006 · 3.32 Impact Factor
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    • "Given that the mechanism and site of action of Npro is poorly understood, we investigated its cellular distribution when expressed alone in cells following induction of cellular stress, since virus entry is known to activate the cellular stress pathway to induce the innate response [19]. Initially, Npro relocated to tubular mitochondria, and the pro-apoptotic protein Bax remained cytoplasmic with the subsequent inhibition of apoptosis. "
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    ABSTRACT: The N-terminal protease of pestiviruses, N(pro) is a unique viral protein, both because it is a distinct autoprotease that cleaves itself from the following polyprotein chain, and also because it binds and inactivates IRF3, a central regulator of interferon production. An important question remains the role of N(pro) in the inhibition of apoptosis. In this study, apoptotic signals induced by staurosporine, interferon, double stranded RNA, sodium arsenate and hydrogen peroxide were inhibited by expression of wild type N(pro), but not by mutant protein N(pro) C112R, which we show is less efficient at promoting degradation of IRF3, and led to the conclusion that N(pro) inhibits the stress-induced intrinsic mitochondrial pathway through inhibition of IRF3-dependent Bax activation. Both expression of N(pro) and infection with Bovine Viral Diarrhea Virus (BVDV) prevented Bax redistribution and mitochondrial fragmentation. Given the role played by signaling platforms during IRF3 activation, we have studied the subcellular distribution of N(pro) and we show that, in common with many other viral proteins, N(pro) targets mitochondria to inhibit apoptosis in response to cell stress. N(pro) itself not only relocated to mitochondria but in addition, both N(pro) and IRF3 associated with peroxisomes, with over 85% of N(pro) puncta co-distributing with PMP70, a marker for peroxisomes. In addition, peroxisomes containing N(pro) and IRF3 associated with ubiquitin. IRF3 was degraded, whereas N(pro) accumulated in response to cell stress. These results implicate mitochondria and peroxisomes as new sites for IRF3 regulation by N(pro), and highlight the role of these organelles in the anti-viral pathway.
    PLoS ONE 02/2014; 9(2):e88838. DOI:10.1371/journal.pone.0088838 · 3.23 Impact Factor
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    • "Much additional work will need to be performed to understand the relationship between SGs and MRV VFs . Many other viruses have been shown to interact with SGs in infected cells in order to replicate effectively ( Lloyd , 2012 ) . Although the mechanisms used by other viruses to interact with the SG pathway vary greatly , it is clear that viral evasion and / or viral subversion of this pathway is an important part of the lifecycle of many viruses . "
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    ABSTRACT: At early times in Mammalian Orthoreovirus (MRV) infection, cytoplasmic inclusions termed stress granules (SGs) are formed as a component of the innate immune response, however, at later times they are no longer present despite continued immune signaling. To investigate the roles of MRV proteins in SG modulation we examined non-structural protein µNS localization relative to SGs in infected and transfected cells. Using a series of mutant plasmids, we mapped the necessary μNS residues for SG localization to amino acids 78 and 79. We examined the capacity of a μNS(78-79) mutant to associate with known viral protein binding partners of μNS and found that it loses association with viral core protein λ2. Finally, we show that while this mutant cannot support de novo viral replication, it is able to rescue replication following siRNA knockdown of μNS. These data suggest that μNS association with SGs, λ2, or both play roles in MRV replication.
    Virology 01/2014; 448C:133-145. DOI:10.1016/j.virol.2013.10.009 · 3.32 Impact Factor
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