Dengue virus affects hundreds of millions of people each year around the world, causing a tremendous social and economic impact on affected countries. The aim of this review is to summarize our current knowledge of the functions, structure, and interactions of the viral capsid protein. The primary role of capsid is to package the viral genome. There are two processes linked to this function: the recruitment of the viral RNA during assembly and the release of the genome during infection. Although particle assembly takes place on endoplasmic reticulum membranes, capsid localizes in nucleoli and lipid droplets. Why capsid accumulates in these locations during infection remains unknown. In this review, we describe available data and discuss new ideas on dengue virus capsid functions and interactions. We believe that a deeper understanding of how the capsid protein works during infection will create opportunities for novel antiviral strategies, which are urgently needed to control dengue virus infections. KeywordsRNA virus; flavivirus; arbovirus; dengue virus; capsid protein; viral encapsidation; viral assembly; lipid droplets DENGUE VIRUSDengue virus (DENV) is the most significant arthropod-borne viral pathogen in humans. The geographical spread and incidence of DENV infections have increased dramatically in recent years. DENV is estimated to cause around 390 million infections per year, placing over 3 billion people at risk of infection (1). In addition to the heavy burden placed on public health, DENV epidemics have a huge economic impact on affected countries.DENV is a member of the Flavivirus genus of the Flaviviridae family (2). The Flavivirus genus includes other important emerging and reemerging human pathogens such as Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus ( JEV), yellow fever virus (YFV), and Saint Louis encephalitis virus (SLEV) (3). Most flaviviruses are arthropodborne; however, vertebrate-and invertebrate-specific viruses are also members of the group (for a recent review see 4). DENV cycles in nature between Aedes mosquito vectors (mainly DISCLOSURE STATEMENTThe authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAedes albopictus and Aedes aegypti ) and humans. Four DENV serotypes (DENV1, DENV2, DENV3, and DENV4) circulate in tropical and subtropical regions of the globe (5). They differ from one another by 25-40% at the amino acid level and are further separated into genotypes. Clinical outcomes for all serotypes can be unapparent or result in a spectrum of diseases ranging from self-limited dengue fever to severe dengue, a potentially lethal hemorrhagic illness. The incidence of dengue disease is growing as the mosquito vector spreads owing to urbanization, population growth, international travel, insufficient mosquito control efforts, and global warming.Although vaccines a...
The process of genome release or uncoating after viral entry is one of the least-studied steps in the flavivirus life cycle. Flaviviruses are mainly arthropod-borne viruses, including emerging and reemerging pathogens such as dengue, Zika, and West Nile viruses. Currently, dengue virus is one of the most significant human viral pathogens transmitted by mosquitoes and is responsible for about 390 million infections every year around the world. Here, we examined for the first time molecular aspects of dengue virus genome uncoating. We followed the fate of the capsid protein and RNA genome early during infection and found that capsid is degraded after viral internalization by the host ubiquitin-proteasome system. However, proteasome activity and capsid degradation were not necessary to free the genome for initial viral translation. Unexpectedly, genome uncoating was blocked by inhibiting ubiquitination. Using different assays to bypass entry and evaluate the first rounds of viral translation, a narrow window of time during infection that requires ubiquitination but not proteasome activity was identified. In this regard, ubiquitin E1-activating enzyme inhibition was sufficient to stabilize the incoming viral genome in the cytoplasm of infected cells, causing its retention in either endosomes or nucleocapsids. Our data support a model in which dengue virus genome uncoating requires a nondegradative ubiquitination step, providing new insights into this crucial but understudied viral process.
Dengue viruses cause the most important human viral disease transmitted by mosquitoes. In recent years, a great deal has been learned about molecular details of dengue virus genome replication; however, little is known about genome encapsidation and the functions of the viral capsid protein. During infection, dengue virus capsid progressively accumulates around lipid droplets by an unknown mechanism. Here, we examined the process by which the viral capsid is transported from the ER membrane, where the protein is synthesized, to lipid droplets. Using different methods of intervention, we found that the GBF1-Arf1/Arf4-COPI pathway is necessary for capsid transport to lipid droplets, while the process is independent of both COPII components and Golgi integrity. The transport was sensitive to brefeldin A, while a drug resistant form of GBF1 was sufficient to restore capsid subcellular distribution in infected cells. The mechanism by which lipid droplets gain or lose proteins is still an open question. Our results support a model in which the virus uses a non-canonical function of the COPI system for capsid accumulation on lipid droplets, providing new ideas for antiviral strategies.
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