Key Points
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Several high-resolution structures of rotavirus proteins and particles have recently been reported. These structures have substantially expanded our understanding of cell entry, genome replication and virion assembly for rotaviruses.
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The rotavirus outer capsid functions as a sensor to effect membrane penetration and allow the viruses to gain access to the host cell cytosol. Structures of the major outer capsid protein suggest a model for triggered disassembly in endosomal vesicles.
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Despite the fact that rotaviruses are non-enveloped viruses, their method of membrane penetration resembles that of membrane fusion for enveloped viruses. Structures of the outer-capsid spike protein in pre- and post-membrane penetration conformations suggest a working model.
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Rotaviruses, like other members of the family Reoviridae, direct RNA transcription from inside a subviral particle that never disassembles in the viral life cycle. This process is presumably triggered by the loss of the outer capsid during entry.
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The assembly of subviral particles occurs in non-membranous cytoplasmic inclusions and is likely to be regulated by several viral non-structural proteins. Assembly of the rotavirus core shell around complexes containing viral positive-sense RNA and RNA polymerase induces conformational changes that trigger synthesis of the double-stranded RNA genome.
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Assembly of the rotavirus outer capsid involves the budding of a subviral particle through the endoplasmic reticulum membrane. Subsequent removal of the membrane from the viral particle is concomitant with the addition of outer capsid proteins. The process of membrane acquisition and removal during assembly is one of the least understood aspects of rotavirus biology.
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The process by which rotaviruses are released from infected cells is also poorly characterized. The mechanism of viral egress is probably cell type specific and may differ in vitro versus in vivo.
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Assembly-mediated regulation of replication is not specific to rotaviruses or to the Reoviridae family. Other viruses, including hepatitis B virus, have been shown to use assembly state intermediates as both checkpoints and triggers to ensure that replication occurs in a controlled and productive manner.
Abstract
Viral replication is rapid and robust, but it is far from a chaotic process. Instead, successful production of infectious progeny requires that events occur in the correct place and at the correct time. Rotaviruses (segmented double-stranded RNA viruses of the Reoviridae family) seem to govern their replication through ordered disassembly and assembly of a triple-layered icosahedral capsid. In recent years, high-resolution structural data have provided unprecedented insight into these events. In this Review, we explore the current understanding of rotavirus replication and how it compares to replication of other Reoviridae family members.
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Change history
09 December 2013
Figure 2 in the above article is based on a copyrighted figure by SIB Swiss Institute of Bioinformatics made available at the following website: http://viralzone.expasy.org/complete_by_species/107.html. The figure was modified with permission and rights to the modified figure are retained by the SIB Swiss Institute of Bioinformatics. The figure legend has been corrected online.
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Acknowledgements
The authors thank N. Leach for careful reading of the manuscript, and S. Harrison, E. Settembre and K. Ogden for helpful discussions. S.D.T. and J.T.P. were supported by the Intramural Research Program of the US National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (grant Z01 AI000788). S.M.M. was supported by the NIAID Intramural Research Program and the Virginia Tech Carilion Research Institute (Roanoke, USA).
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Glossary
- Segmented
-
Pertaining to a virus: with a genome comprising multiple distinct nucleic acid molecules; each segment is analogous to a eukaryotic chromosome, but usually encodes only 1–3 proteins.
- Icosahedral
-
With 30 two-fold, 20 three-fold and 12 five-fold axes of rotation (like an icosahedron or a dodecahedron). A type of symmetry common to viral capsids.
- Positive-sense RNAs
-
((+)RNAs). The RNA strands that directly encode the viral proteins and are used as templates to synthesize the negative-sense strands during replication of the genome.
- Triangulation number
-
(T number). The number of symmetrically distinct subunits that make up each of the asymmetric units of the capsid. Generally, larger virions require higher T numbers (that is, more subunits) to form their capsids.
- Five-fold vertices
-
The points on an icosahedron; for viruses of the family Reoviridae, these are the 12 axes of five-fold symmetry and the sites of positive-sense RNA extrusion.
- RNA-capping enzyme
-
An enzyme that is responsible for modifying the 5′ end of an RNA to generate a cap structure that is similar to that of eukaryotic mRNAs.
- Peripentonal channels
-
For rotaviruses, the approximately six-fold-symmetrical 'gaps' in the VP6 layer that surround each of the five-fold vertices. These channels are the binding sites for VP4 trimers during assembly of the viral particle.
- Serotype
-
A classification of rotaviruses using comparative neutralization by monoclonal antibodies; for rotaviruses, there are two outer capsid proteins (VP4 and VP7), giving a binary serotype.
- Neutralizing antibodies
-
Antibodies that block infectivity (for example, of a virus), usually by binding to the foreign particle (the virion) and incapacitating it in some way.
- Galectin
-
A family of sugar-binding proteins that have a similar, distinct fold.
- Sialic acid moieties
-
Carbohydrate functional groups added to proteins or lipids. These groups are used by several viruses (including rotaviruses and influenza viruses) as attachment factors to facilitate attachment to host cells.
- Myristoylated
-
Of a protein: with an amino terminus that has a covalently linked myristic acid fatty acid. This can impart a hydrophobic character to a protein or target it to a membrane.
- Cathepsin
-
A diverse family of intracellular proteases, many members of which function in the low pH environment of the lysosome.
- Negative-sense RNAs
-
The reverse complement of the positive-sense RNAs; for the Reoviridae family viruses, the negative-sense strand is used as a template during transcription to make more positive-sense RNA.
- Reverse genetics systems
-
Methods of specifically modifying a viral genome using recombinant technology (versus a forward genetics screen).
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Trask, S., McDonald, S. & Patton, J. Structural insights into the coupling of virion assembly and rotavirus replication. Nat Rev Microbiol 10, 165–177 (2012). https://doi.org/10.1038/nrmicro2673
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DOI: https://doi.org/10.1038/nrmicro2673
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