Abstract
Flaviviruses are enveloped positive-sense single-stranded RNA arboviruses, infectious to humans and many other animals and are transmitted primarily via tick or mosquito vectors. Capsid is the primary structural protein to interact with viral genome within virus particles and is therefore necessary for efficient packaging. However, in cells, capsid interacts with many proteins and nucleic acids and we are only beginning to understand the broad range of functions of flaviviral capsids. It is known that capsid dimers interact with the membrane of lipid droplets, aiding in both viral packaging and storage of capsid prior to packaging. However, capsid dimers can bind a range of nucleic acid templates in vitro, and likely interact with a range of targets during the flavivirus lifecycle. Capsid may interact with host RNAs, resulting in altered RNA splicing and RNA transcription. Capsid may also bind short interfering-RNAs and has been proposed to sequester these species to protect flaviviruses from the invertebrate siRNA pathways. Capsid can also be found in the nucleolus, where it wreaks havoc on ribosome biogenesis. Here we review flavivirus capsid structure, nucleic acid interactions and how these give rise to multiple functions. We also discuss how these features might be exploited either in the design of effective antivirals or novel vaccine strategies.
Highlights
Flaviviruses are arthropod-borne viruses that plague both tropic and sub-tropic regions
It appears that capsid proteins are stored on lipid droplets in the cytoplasm and mobilized for RNA packaging when needed, as lipids are constantly shuffled between the endoplasmic reticulum (ER) membrane and lipid droplets
When placed into the context of the viral life cycle it is interesting to consider the various interactions of flavivirus capsid proteins
Summary
Flaviviruses are arthropod-borne viruses that plague both tropic and sub-tropic regions. The capsid protein’s ability to leave the replication factories is interesting, and coupled with their ability to bind various nucleic acids (and host proteins) [35,36], suggests that flavivirus capsid may have multiple evolved functions beyond viral packaging The result of these interactions can result in either the activation or repression of various pathways with deleterious effects, including apoptosis or cell cycle arrest [19,37]. Flavivirus genome structure and replication strategies are largely the same, this review focuses on the mosquito-borne flaviviruses These viruses are more globally distributed than that of the tick-borne viruses such as tick-borne encephalitis virus [2,41], and crystal structures for capsid have been solved for ZIKV, JEV, and WNV [35,42,43]. A greater understanding of these interactions and their implications should lead to insightful drug and vaccine design
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