Post-translational regulation and modifications of flavivirus structural proteins

Abstract

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 ...

Cytoarchitecture of Zika virus infection in human neuroblastoma and Aedes albopictus cell lines

“…The particles are transported to and traverse the Golgi structures, acquiring glycosylation. Finally, in a post-Golgi vesicle, the covalent attachment between the preM and E structural proteins is cleaved by furin and the mature virion is formed and exits the cell (17). …”

Valosin-containing protein (VCP/p97) plays a role in the replication of West Nile virus

“…Encapsidation of nascent viral genomic RNA is achieved by the capsid protein and budding into the ER yielding a viral envelope coated with prM and E proteins (Brinton, 2014;Fields et al, 2013;Suthar et al, 2013;Welsch et al, 2009). The immature virions are transported via the host secretory pathway and virion maturation then occurs in the acidic compartments of the Golgi by cleavage of the prM protein by a furin-like protease (Plevka et al, 2014;Roby et al, 2015;Yu et al, 2008). Mature virions are then released from the infected cells through exocytosis (Fields et al, 2013;Samuel and Diamond, 2006).…”

Sublingual immunization with Japanese encephalitis virus vaccine effectively induces immunity through both cellular and humoral immune responses in mice

“…This single polyprotein is cleaved co‐ and post‐translationally by viral and host proteases to form both structural and nonstructural viral proteins. This is an essential step in producing infectious progeny viruses .…”