Article

Hijacking Components of the Cellular Secretory Pathway for Replication of Poliovirus RNA

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-8011, USA.
Journal of Virology (Impact Factor: 4.44). 02/2007; 81(2):558-67. DOI: 10.1128/JVI.01820-06
Source: PubMed

ABSTRACT

Infection of cells with poliovirus induces a massive intracellular membrane reorganization to form vesicle-like structures where viral RNA replication occurs. The mechanism of membrane remodeling remains unknown, although some observations have implicated components of the cellular secretory and/or autophagy pathways. Recently, we showed that some members of the Arf family of small GTPases, which control secretory trafficking, became membrane-bound after the synthesis of poliovirus proteins in vitro and associated with newly formed membranous RNA replication complexes in infected cells. The recruitment of Arfs to specific target membranes is mediated by a group of guanine nucleotide exchange factors (GEFs) that recycle Arf from its inactive, GDP-bound state to an active GTP-bound form. Here we show that two different viral proteins independently recruit different Arf GEFs (GBF1 and BIG1/2) to the new structures that support virus replication. Intracellular Arf-GTP levels increase approximately 4-fold during poliovirus infection. The requirement for these GEFs explains the sensitivity of virus growth to brefeldin A, which can be rescued by the overexpression of GBF1. The recruitment of Arf to membranes via specific GEFs by poliovirus proteins provides an important clue toward identifying cellular pathways utilized by the virus to form its membranous replication complex.

Download full-text

Full-text

Available from: Catherine Jackson
  • Source
    • "A switch of target from viral proteins to host factors may be a promising approach, as this would reduce the risk of emergence of enterovirus resistance. The genomic RNA replication of enteroviruses has been shown to occur in membranous vesicles resembling coat protein complex (COPI and COPII)-coated transport vesicles derived from the host secretory pathway during early infection891011. During late infection, there is a switch to membranes derived from autophagosomes, the degradative compartments of the autophagic machinery, for viral assembly, maturation, and exit from host cells12131415. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Enterovirus genus of the Picornaviridae family comprises many important human pathogens, including polioviruses, rhinovirus, enterovirus A71, and enterovirus D68. They cause a wide variety of diseases, ranging from mild to severe life-threatening diseases. Currently, no effective vaccine is available against enteroviruses except for poliovirus. Enteroviruses subvert the autophagic machinery to benefit their assembly, maturation, and exit from host. Some enteroviruses spread between cells via a process described as autophagosome-mediated exit without lysis (AWOL). The early and late phases of autophagy are regulated through various lipids and their metabolizing enzymes. Some of these lipids and enzymes are specifically regulated by enteroviruses. In the present review, we summarize the current understanding of the regulation of autophagic machinery by enteroviruses, and provide updates on recent developments in this field.
    Full-text · Article · Jan 2016 · Viruses
  • Source
    • "CVB redirects a number of cell host factors to remodel intracellular membranes for efficient viral replication (Wessels et al., 2007; Hsu et al., 2010; Lanke et al., 2009). These host proteins include phosphatidylinositol-4-kinase (PI4KIIIβ), guanine nucleotide exchange factor – GBF1, and ARF1 which help to assemble the membrane replication complex supporting CVB and PV infection (Belov et al., 2007; Lanke et al., 2009). The current model for the initiation of CVB replication organelles in the host cell involves the recruitment of PI4KIIIβ following viral protein 3A binding to GBF1/Arf1 as COPI, a protein that regulates membrane budding, is displaced. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Oct 2015 · Virology
  • Source
    • "During this process, enteroviruses hijack a number of host cell factors, including GBF1 and PI4KIIIb (Belov et al., 2007; Hsu et al., 2010; Lanke et al., 2009). Replication organelles of enteroviruses are enriched in PI4P lipids produced by PI4KIIIb (Hsu et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Enteroviruses, e.g., polio-, coxsackie- and rhinoviruses, constitute a large genus within the Picornaviridae family of positive-strand RNA viruses and include many important pathogens linked to a variety of acute and chronic diseases. Despite their huge medical and economic impact, no approved antiviral therapy is yet available. Recently, the oxysterol-binding protein (OSBP) was implicated as a host factor for enterovirus replication. Here, we investigated the antiviral activity of the natural compound OSW-1, a ligand of OSBP that is under investigation as an anti-cancer drug. OSW-1 potently inhibited the replication of all enteroviruses tested, with IC50 values in the low nanomolar range, acted at the genome replication stage and was effective in all tested cell types of three different species. Importantly, OSBP overexpression rescued viral replication, demonstrating that the antiviral effect of OSW-1 is due to targeting OSBP. Together, we here report the anti-enterovirus activity of the natural anti-cancer compound OSW-1. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · Antiviral Research
Show more