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Review
. 2012 Dec;2(6):740-7.
doi: 10.1016/j.coviro.2012.09.006. Epub 2012 Oct 1.

(+)RNA viruses rewire cellular pathways to build replication organelles

George A Belov  1 , Frank J M van Kuppeveld
Affiliations
Review

(+)RNA viruses rewire cellular pathways to build replication organelles

George A Belov et al. Curr Opin Virol. 2012 Dec.

Abstract

Positive-strand RNA [(+)RNA] viruses show a significant degree of conservation of their mechanisms of replication. The universal requirement of (+)RNA viruses for cellular membranes for genome replication, and the formation of membranous replication organelles with similar architecture, suggest that they target essential control mechanisms of membrane metabolism conserved among eukaryotes. Recently, significant progress has been made in understanding the role of key host factors and pathways that are hijacked for the development of replication organelles. In addition, electron tomography studies have shed new light on their ultrastructure. Collectively, these studies reveal an unexpected complexity of the spatial organization of the replication membranes and suggest that (+)RNA viruses actively change cellular membrane composition to build their replication organelles.

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Figures

Figure 1
Figure 1
Basic principles of viral replication organelle organization. (a–d) Invagination type of replication organelles with negative membrane curvature typical for flavi-like and alpha-like viruses. Arrowheads show connection of the inner compartment with the cytoplasm. (a) EM image and tomography reconstruction of the replication structures of Dengue virus induced on ER membranes (modified from [3]). (b) EM image and tomography reconstruction of the replication structures of Flock house virus on outer mitochondria membrane (modified from [2]). (c) Spherules induced on the plasma membrane at the early stage of Semliki Forest virus infection are later translocated inside the cytoplasm (modified from [17]). (d) Schematic representation of the invagination–spherule replication organelle organization. (e–g) Vesicular–tubular replication organelles with positive membrane curvature characteristic of picorna-like viruses. (e) EM image and tomography reconstruction of the early replication structures of poliovirus (modified from [4]). (f) EM image and tomography reconstruction of the early replication structures of Coxsackie B3 virus (modified from [5]). (g) Schematic representation of the vesicular–tubular replication organelle organization.
Figure 2
Figure 2
Schematic overview of the secretory pathway and the sites targeted and/or altered by (+)RNA viruses for formation of their membranous replication organelles. For reasons of simplicity, the endocytic pathway and the lysosomes are combined. Secretory pathway transport depends on specific coat complexes that contribute by mediating the bending, deformation and detachment of membranes carriers. Anterograde transport of proteins out of the ER takes place via a COP-II dependent pathway, whereas intra-Golgi transport as well as retrograde transport from the Golgi and intermediated compartment relies on COP-I-coated carries. Endocytosis takes place via clathrin-coated vesicles. The putative sites that are targeted and/or altered by different (+)RNA viruses (Family and Genera names of the viruses are given here below between parenthesis) to form their replication organelles are indicated by their position. Essential host factors and their localization are also indicated. CV, coxsackievirus (Picornaviridae, Enterovirus). DENV, dengue virus (Flaviviridae, Flavivirus). EAV, equine arteritis virus (Arteriviridae, Arterivirus). FHV, flock house virus (Nodaviridae, Alphanodavirus). HCV, hepatitis C virus (Flaviviridae, Hepacivirus). MHV, mouse hepatitis virus (Coronaviridae, Coronavirus). PV, poliovirus (Picornaviridae, Enterovirus). RUBV, rubella virus (Togaviridae, Rubivirus). SARS-CoV, severe acute respiratory syndrome coronavirus (Coronaviridae, Coronavirus). SFV, Semliki Forest virus (Togaviridae, Alphavirus). TBSV, tomato bushy stunt virus (Tombusviridae, Tombusvirus). TMV, tobacco mosaic virus (Virgaviridae, Tobamovirus). WNV, west Nile virus (Flaviviridae, Flavivirus).
Figure 3
Figure 3
Possible functions of GBF1 and PI4KIIIβ/PI4P in formation and/or activity of enterovirus replication organelles. Enterovirus replication starts at Golgi membranes where the viral 3A protein interacts with GBF1, a GEF for Arf1 that in uninfected cells is involved in recruiting COP-I coats to membranes (left). The interaction of 3A with GBF1 interferes with COP-I recruitment, resulting in uncoated membranes that can no longer function in secretory pathway trafficking. At the same time, 3A causes an increased recruitment of PI4KIIIβ to membranes. Although this lipid kinase is an effector of Arf1 in uninfected cells, growing evidence suggests that the interaction of 3A with GBF1/Arf1 is not essential for the massive recruitment of PI4KIIIβ observed in infected cells. 3A may directly interact with PI4KIIIβ or this interaction may occur via another cellular protein (e.g. ACBD3, which has recently been reported to bind 3A as well as PI4KIIIβ [68, 69]). Enhanced recruitment of PI4KIIIβ results in PI4P enriched membranes, which may serve to activate and/or recruit viral and/or cellular proteins that are directly involved in replication of the viral RNA. One candidate protein is the viral RNA-dependent RNA polymerase, 3D, which has been shown to bind PI4P lipids in vitro. Additionally, PI4P-rich membranes may serve as docking sites for other cellular proteins that exert functions in membrane remodeling that contribute to the formation of the membranous environment suitable for RNA replication.
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