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


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.

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    • "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. "
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    • "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. "
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