Architects of assembly: roles of Flaviviridae non-structural proteins in virion morphogenesis

Murray, Catherine; Jones, Christopher T.; Rice, Charles M.

doi:10.1038/nrmicro1928

Cited by 206 publications

(174 citation statements)

References 108 publications

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“…The exact nature of nucleocapsid assembly remains elusive, as the nucleocapsids themselves display no inherent order to their structure (Kiermayr et al, 2004;Kuhn et al, 2002;Ló pez et al, 2009;Zhang et al, 2007b) and a physical interaction of the nucleocapsid with the envelope is not observed. In accordance, the production of empty prM/E particles during virus infection (Lindenbach et al, 2007;Murray et al, 2008) and when these genes are expressed in the absence of C (Allison et al, 1995(Allison et al, , 2003Konishi & Mason, 1993;Lorenz et al, 2003;Wang et al, 2009) suggests that prM/E formation and nucleocapsid assembly are independent processes. However, the efficiency of C dimerization impacts on the overall integrity of the assembled particle in a thermal stability assay (Patkar et al, 2007), suggesting that some interaction between C and prM/E does still occur in the virion.…”

Section: Formation Of the Nucleocapsidmentioning

confidence: 84%

Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

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Flaviviruses are a group of single-stranded, positive-sense RNA viruses that generally circulate between arthropod vectors and susceptible vertebrate hosts, producing significant human and veterinary disease burdens. Intensive research efforts have broadened our scientific understanding of the replication cycles of these viruses and have revealed several elegant and tightly co-ordinated post-translational modifications that regulate the activity of viral proteins. The three structural proteins in particular -capsid (C), pre-membrane (prM) and envelope (E) -are subjected to strict regulatory modifications as they progress from translation through virus particle assembly and egress. The timing of proteolytic cleavage events at the C-prM junction directly influences the degree of genomic RNA packaging into nascent virions. Proteolytic maturation of prM by host furin during Golgi transit facilitates rearrangement of the E proteins at the virion surface, exposing the fusion loop and thus increasing particle infectivity. Specific interactions between the prM and E proteins are also important for particle assembly, as prM acts as a chaperone, facilitating correct conformational folding of E. It is only once prM/E heterodimers form that these proteins can be secreted efficiently. The addition of branched glycans to the prM and E proteins during virion transit also plays a key role in modulating the rate of secretion, pH sensitivity and infectivity of flavivirus particles. The insights gained from research into post-translational regulation of structural proteins are beginning to be applied in the rational design of improved flavivirus vaccine candidates and make attractive targets for the development of novel therapeutics. FlavivirusesThe genus Flavivirus in the family Flaviviridae comprises small, enveloped viruses with non-segmented genomes consisting of single-stranded, positive-sense RNA. These RNA genomes are flanked by 59 and 39 untranslated regions (UTRs) and encode a single polyprotein that is cleaved coand post-translationally to generate between 10 and 11 viral proteins. The 59 UTR contains a type 1 m 7 GpppNm cap structure and the 39 UTR lacks a polyadenylated tail. Structural elements within the UTRs regulate genome replication, translation and host immune responses. Viral proteins are divided between structural proteins, which form the virion, and non-structural proteins, which are involved in genomic replication and modulating host immunity (Fig. 1a) (Lindenbach et al., 2007;Roby et al., 2012).Flaviviruses are maintained predominantly in natural transmission cycles between vertebrate reservoir species (normally mammalian or avian) and haematophagous arthropod vectors (mosquitoes or ticks). Notable exceptions are the viruses that are maintained solely in mosquito hosts (insectspecific flaviviruses) and viruses with no known invertebrate vector (Cook et al., 2012;Mackenzie et al., 2004). As of 2013, the International Committee on Taxonomy of Viruses has classified 53 different viral species as belonging to ...

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Section: Formation Of the Nucleocapsidmentioning

confidence: 84%

Post-translational regulation and modifications of flavivirus structural proteins

Roby

Setoh

Hall

et al. 2015

Journal of General Virology

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“…The entry module contains at least the capsid (Core) and envelope (E1 and E2) proteins. Finally, the assembly module is more difficult to describe since Flaviviridae use, in addition to the structural proteins that constitute the bricks for assembly, some of the non-structural proteins to orchestrate this process [18,19]. The overlap between the different modules illustrates the multifunctionality of HCV proteins, a solution for the challenges associated with a very small genome.…”

Section: Molecular Virology Of Hcvmentioning

confidence: 99%

Entry and replication of recombinant hepatitis C viruses in cell culture

Vièyres

Pietschmann

2013

Methods

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“…HCV is a member of the Flaviviridae family, which contains the Hepacivirus, Flavivirus and Pestivirus genera [50]. While there is a diversity of viruses within this family-dengue, classical swine fever, and viral encephalitis are just a few examples-there are also important common features: they are all small, lipid-enveloped RNA viruses and have many analogous steps in the viral life cycle including host cell entry, viral polyprotein processing, and viral genome replication [51]. Indeed, similar to other Flaviviridae members, HCV is a positive singlestranded RNA virus with a 9.6 kb genome that encodes for a 3010-amino acid long polyprotein [52] (Fig.…”

Section: Challenges Of Hepatitis C Drug Developmentmentioning

confidence: 99%

Model Membrane Platforms for Biomedicine: Case Study on Antiviral Drug Development

Jackman

Cho

2012

Biointerphases

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As one of the most important interfaces in cellular systems, biological membranes have essential functions in many activities such as cellular protection and signaling. Beyond their direct functions, they also serve as scaffolds to support the association of proteins involved in structural support, adhesion, and transport. Unfortunately, biological processes sometimes malfunction and require therapeutic intervention. For those processes which occur within or upon membranes, it is oftentimes difficult to study the mechanism in a biologically relevant, membranous environment. Therefore, the identification of direct therapeutic targets is challenging. In order to overcome this barrier, engineering strategies offer a new approach to interrogate biological activities at membrane interfaces by analyzing them through the principles of the interfacial sciences. Since membranes are complex biological interfaces, the development of simplified model systems which mimic important properties of membranes can enable fundamental characterization of interaction parameters for such processes. We have selected the hepatitis C virus (HCV) as a model viral pathogen to demonstrate how model membrane platforms can aid antiviral drug discovery and development. Responsible for generating the genomic diversity that makes treating HCV infection so difficult, viral replication represents an ideal step in the virus life cycle for therapeutic intervention. To target HCV genome replication, the interaction of viral proteins with model membrane platforms has served as a useful strategy for target identification and characterization. In this review article, we demonstrate how engineering approaches have led to the discovery of a new functional activity encoded within the HCV nonstructural 5A protein. Specifically, its N-terminal amphipathic, α-helix (AH) can rupture lipid vesicles in a size-dependent manner. While this activity has a number of exciting biotechnology and biomedical applications, arguably the most promising one is in antiviral medicine. Based on the similarities between lipid vesicles and the lipid envelopes of virus particles, experimental findings from model membrane platforms led to the prediction that a range of medically important viruses might be susceptible to rupturing treatment with synthetic AH peptide. This hypothesis was tested and validated by molecular virology studies. Broad-spectrum antiviral activity of the AH peptide has been identified against HCV, HIV, herpes simplex virus, and dengue virus, and many more deadly pathogens. As a result, the AH peptide is the first in class of broad-spectrum, lipid envelope-rupturing antiviral agents, and has entered the drug pipeline. In summary, engineering strategies break down complex biological systems into simplified biomimetic models that recapitulate the most important parameters. This approach is particularly advantageous for membrane-associated biological processes because model membrane platforms provide more direct characterization of target interactions than is possible with other methods. Consequently, model membrane platforms hold great promise for solving important biomedical problems and speeding up the translation of biological knowledge into clinical applications.

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Architects of assembly: roles of Flaviviridae non-structural proteins in virion morphogenesis

Cited by 206 publications

References 108 publications

Post-translational regulation and modifications of flavivirus structural proteins

Post-translational regulation and modifications of flavivirus structural proteins

Entry and replication of recombinant hepatitis C viruses in cell culture

Model Membrane Platforms for Biomedicine: Case Study on Antiviral Drug Development

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