The many faces of the flavivirus NS1 protein offer a multitude of options for inhibitor design

Watterson, Daniel; Modhiran, Naphak; Young, Paul R.

doi:10.1016/j.antiviral.2016.02.014

Cited by 114 publications

(119 citation statements)

References 116 publications

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“…Of these proteins, only NS1 and NS4B have cysteines that are conserved across all four DENV serotypes. The DENV protein NS1 forms a dimer in the ER, is secreted as a soluble hexamer, and contains twelve cysteines, six disulfide bonds, and two N-glycosylation sites (14). The DENV protein NS4B contains three cysteines and two N-glycosylation sites (15).…”

Section: Resultsmentioning

confidence: 99%

Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex

Lin

Cherepanova

Bozzacco

et al. 2017

mBio

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Dengue virus (DENV) is the most common arboviral infection globally, infecting an estimated 390 million people each year. We employed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screen to identify host dependency factors required for DENV propagation and identified the oligosaccharyltransferase (OST) complex as an essential host factor for DENV infection. Mammalian cells express two OSTs containing either STT3A or STT3B. We found that the canonical catalytic function of the OSTs as oligosaccharyltransferases is not necessary for DENV infection, as cells expressing catalytically inactive STT3A or STT3B are able to support DENV propagation. However, the OST subunit MAGT1, which associates with STT3B, is also required for DENV propagation. MAGT1 expression requires STT3B, and a catalytically inactive STT3B also rescues MAGT1 expression, supporting the hypothesis that STT3B serves to stabilize MAGT1 in the context of DENV infection. We found that the oxidoreductase CXXC active site motif of MAGT1 was necessary for DENV propagation, as cells expressing an AXXA MAGT1 mutant were unable to support DENV infection. Interestingly, cells expressing single-cysteine CXXA or AXXC mutants of MAGT1 were able to support DENV propagation. Utilizing the engineered peroxidase APEX2, we demonstrate the close proximity between MAGT1 and NS1 or NS4B during DENV infection. These results reveal that the oxidoreductase activity of the STT3B-containing OST is necessary for DENV infection, which may guide the development of antiviral agents targeting DENV.

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Section: Resultsmentioning

confidence: 99%

Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex

Lin

Cherepanova

Bozzacco

et al. 2017

mBio

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“…Nonetheless, these proteins are fast evolving in ZIKV and related flaviviruses, and the numerous selected sites are expected to entail functional differences among closely related viruses or even among viruses belonging to the same species. Thus, our data suggest that compounds developed against DENV NS4B [42] or drugs that result in DENV NS1 misfolding [75, 76] may not be active against ZIKV.…”

Section: Discussionmentioning

confidence: 98%

“…Finally, we note that NS1 and NS4B are regarded as attractive candidates as direct or indirect targets for antiviral drugs in flavivirus infections [42, 75]. Nonetheless, these proteins are fast evolving in ZIKV and related flaviviruses, and the numerous selected sites are expected to entail functional differences among closely related viruses or even among viruses belonging to the same species.…”

Section: Discussionmentioning

confidence: 99%

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

et al. 2016

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The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian/American ZIKV lineage.

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“…The flavivirus positive-sense RNA genome encodes three structural proteins, which form the virus particle, and seven nonstructural proteins, which perform essential functions in genome replication, polyprotein processing, and manipulation of cellular processes to viral advantage. Flavivirus nonstructural protein 1 (NS1), one of only ten viral proteins, is a multi-functional virulence factor 8,9 . Within an infected cell, the glycosylated 48-kDa NS1 is a membrane-associated dimer following translocation into the endoplasmic reticulum (ER) lumen, where it is essential for viral genome replication.…”

mentioning

confidence: 99%

Extended surface for membrane association in Zika virus NS1 structure

Brown

Akey

Konwerski

et al. 2016

Nat Struct Mol Biol

158

219

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The Zika virus, which is implicated in an increase in neonatal microcephaly and Guillain-Barré syndrome, has spread rapidly through tropical regions of the world. The virulence protein NS1 functions in genome replication and host immune system modulation. Here we report the crystal structure of full-length Zika virus NS1, revealing an elongated hydrophobic surface for membrane association and a polar surface that varies substantially among flaviviruses.

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The many faces of the flavivirus NS1 protein offer a multitude of options for inhibitor design

Cited by 114 publications

References 116 publications

Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex

Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

Extended surface for membrane association in Zika virus NS1 structure

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