Dengue NS2A Protein Orchestrates Virus Assembly

Xie, Xuping; Zou, Jing; Zhang, Xianwen; Zhou, Yiyang; Routh, Andrew; Kang, CongBao; Popov, Vsevolod L.; Chen, Xinwen; Wang, Qing Yin; Dong, Hansong; Shi, Pei Yong

doi:10.1016/j.chom.2019.09.015

Cited by 79 publications

(93 citation statements)

References 68 publications

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“…These mutants, which were incompetent for viral assembly, (Gly-11-Ala, Glu-20-Ala, Glu-100-Ala, Gln-187-Ala, and Lys-188-Ala), could be rescued in trans by expressing wild-type NS2A or a mutant unable to support vRNA replication [86]. Further studies demonstrated that despite similar levels of viral protein synthesis and ER membrane rearrangements between wild-type RNA and the Gly-11-Ala mutant, the latter failed to form viral particles, as assessed by transmission electron microscopy, and reduced release of extracellular vRNA [87]. Moreover, the Gly-11-Ala mutant showed a significant decrease in the C-prM cleavage which resulted in an altered cellular localization of C, a decreased expression of E and an abrogation of prM expression.…”

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

“…More recently, a detailed mechanism of the function for NS2A during DENV virus assembly was described by Xie and collaborators [86,87]. The authors reported a set of mutations that specifically impaired virus assembly without affecting vRNA synthesis.…”

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

“…Indeed, overexpression of DENV and JEV NS2A in E. coli resulted in increased membrane permeability and lysis [89,91]; however, more recent studies point towards a different mechanism by which NS2A transports newly synthesized vRNA. In their study, Xie and collaborators [87] showed that NS2A specifically binds to DENV vRNA, with a cytoplasmic loop of NS2A (amino acids 93 to 100) interacting with the last 285 nucleotides of DENV 3′ UTR. Similar findings were reported by the same group for ZIKA NS2A, where the cytoplasmic loop (residues 97 to 104) was shown to interact with the last 333 nucleotides from the 3′ UTR [88].…”

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

“…These molecules are brought together due to oligomerization of NS2A after which processing of the structural proteins occurs yielding free C that binds to vRNA to form the nucleocapsid on the cytoplasmic side. The nucleocapsid is then enveloped by E and prM leading to virion formation and budding into the ER lumen [87,88]. Although the proposed model is very compelling, it remains to be addressed whether interaction of the vRNA with C will lead to its detachment from NS2A, or whether NS2A is incorporated into the virion.…”

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

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Role of RNA-binding proteins during the late stages of Flavivirus replication cycle

Diosa-Toro

Prasanth

Bradrick

et al. 2020

Virol J

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The genus Flavivirus encompasses several worldwide-distributed arthropod-borne viruses including, dengue virus, Japanese encephalitis virus, West Nile virus, yellow fever virus, Zika virus, and tick-borne encephalitis virus. Infection with these viruses manifest with symptoms ranging from febrile illness to life-threatening hypotensive shock and encephalitis. Therefore, flaviviruses pose a great risk to public health. Currently, preventive measures are falling short to control epidemics and there are no antivirals against any Flavivirus. Flaviviruses carry a single stranded positive-sense RNA genome that plays multiple roles in infected cells: it is translated into viral proteins, used as template for genome replication, it is the precursor of the subgenomic flaviviral RNA and it is assembled into new virions. Furthermore, viral RNA genomes are also packaged into extracellular vesicles, e.g. exosomes, which represent an alternate mode of virus dissemination. Because RNA molecules are at the center of Flavivirus replication cycle, viral and host RNA-binding proteins (RBPs) are critical determinants of infection. Numerous studies have revealed the function of RBPs during Flavivirus infection, particularly at the level of RNA translation and replication. These proteins, however, are also critical participants at the late stages of the replication cycle. Here we revise the function of host RBPs and the viral proteins capsid, NS2A and NS3, during the packaging of viral RNA and the assembly of new virus particles. Furthermore, we go through the evidence pointing towards the importance of host RBPs in mediating cellular RNA export with the idea that the biogenesis of exosomes harboring Flavivirus RNA would follow an analogous pathway.

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Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

Section: Post-replicative Functions Of Ns Proteinsmentioning

confidence: 99%

See 2 more Smart Citations

Role of RNA-binding proteins during the late stages of Flavivirus replication cycle

Diosa-Toro

Prasanth

Bradrick

et al. 2020

Virol J

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“…Specific mutations in NS2A appear to hinder packaging [28,29]. It has recently been shown that dengue and ZIKV NS2A recruits the viral genome by binding specifically to the highly-structured 3 UTR and the C-prM-E complex and protease to site of virion assembly coordinating capsid loading and subsequent virion assembly [30,31]. The NS3 helicase separates nascent (+) strand from template (−) strand starting at the 3 end [32] and NS5 binds the 5 UTR of the (+) sense viral genome and translocates to the 3 end upon cyclization of the RNA to begin genome replication [33,34].…”

Section: Introductionmentioning

confidence: 99%

Understanding Flavivirus Capsid Protein Functions: The Tip of the Iceberg

Sotcheff

Routh

2020

Pathogens

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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.

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Characterization and in vitro assembly of tick‐borne encephalitis virus C protein

et al. 2020

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Tick‐borne encephalitis virus (TBEV), a member of flaviviruses, represents a serious health threat by causing human encephalitis mainly in central and eastern Europe, Russia, and northeastern Asia. As no specific therapy is available, there is an urgent need to understand all steps of the TBEV replication cycle at the molecular level. One of the critical events is the packaging of flaviviral genomic RNA by TBEV C protein to form a nucleocapsid. We purified recombinant TBEV C protein and used a combination of physical–chemical approaches, such as size‐exclusion chromatography, circular dichroism, NMR spectroscopies, and transmission electron microscopy, to analyze its structural stability and its ability to dimerize/oligomerize. We compared the ability of TBEV C protein to assemble in vitro into a nucleocapsid‐like structure with that of dengue C protein.

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Dengue NS2A Protein Orchestrates Virus Assembly

Abstract: Highlights d Dengue NS2A recruits C-prM-E structural proteins and a protease to virion assembly site d A cytosolic loop of NS2A recruits the 3 0 UTR of viral RNA to virion assembly site d A coordinated C-prM cleavage enables viral RNA encapsidation and virion formation

Cited by 79 publications

References 68 publications

Role of RNA-binding proteins during the late stages of Flavivirus replication cycle

Role of RNA-binding proteins during the late stages of Flavivirus replication cycle

Understanding Flavivirus Capsid Protein Functions: The Tip of the Iceberg

Characterization and in vitro assembly of tick‐borne encephalitis virus C protein

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