Flavivirus NS4B protein: Structure, function, and antiviral discovery

Wang, Yan; Xie, Xuping; Shi, Pei–Yong

doi:10.1016/j.antiviral.2022.105423

Cited by 16 publications

(6 citation statements)

References 105 publications

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“…Structural analysis showed that ZIKV-1555 NS4B residues 1 to 16 and 35 to 50 have propensity for forming a-helical structure and transmembrane helix, respectively. The NS4B amino-acid substitutions at positions 20, 24, and 26 that differentiate ZIKV-15555 from MR766 have been identified in a non-ordered structure between helix a1 and TM1 (29).…”

Section: Resultsmentioning

confidence: 99%

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The replication properties of a contemporary Zika virus from West Africa depends on NS1/NS4B proteins

Machmouchi,

Courageot,

El-Kalamouni

et al. 2024

Preprint

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Zika virus (ZIKV) have become a global health problem over the past decade due to the extension of the geographic distribution of ZIKV of Asian genotype. Epidemics of Asian ZIKV have been associated with developmental disorders in humans. ZIKV of African lineage would have an epidemic potential associated to fetal pathogenicity requiring a greater attention towards the most recently isolated viral strains from West Africa. In the present study, an infectious molecular clone GUINEA-18 has been obtained from viral strain ZIKV-15555 that had been sequenced from an individual infected by ZIKV in Guinea in 2018. A molecular clone-based comparative study between GUINEA-18 and viral clone MR766MC from historical African ZIKV strain MR766 revealed a lower replication rate for GUINEA-18 associated to a weaker cytotoxicity and reduced innate immune system activation in Vero E6, A549 and HCM3 cell lines. Analysis of chimeric viruses between MR766MC and GUINEA-18 stressed the importance NS1/NS4B proteins with a particular focus for NS4B on GUINEA-18 replication properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. Study of G3BP protein showed that GUINEA-18 but not MR766MC was efficient to inhibit stress granule assembly in A549 cells subjected to a physiological stressor. GUINEA-18 depends on NS1/NS4B proteins for suppressing stress granule response to environmental stress. The involvement of GUINEA-18 NS1/NS4B proteins on virus replication capability and host-cell responses to ZIKV infection raises the question of the importance of nonstructural proteins in the pathogenicity of contemporary viral strains from West Africa.

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Section: Resultsmentioning

confidence: 99%

“…amino-acid substitutions at positions 20, 24, and 26 that differentiate ZIKV-15555 from MR766 have been identified in a non-ordered structure between helix a1 and TM1 (29).…”

Section: Ldh Activity (Fold Of Control)mentioning

confidence: 99%

The replication properties of a contemporary Zika virus from West Africa depends on NS1/NS4B proteins

Machmouchi,

Courageot,

El-Kalamouni

et al. 2024

Preprint

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“…NS1, NS4A, and NS4B have all been reported to possess the ability to remodel the ER. NS4A facilitates membrane association and contributes to membrane remodeling [17,18], while NS4B interacts with NS1 or host protein TMEM41B to induce membrane curvature [19,20]. In our previous study, we found that ZIKV NS1 is indispensable for the establishment of RCs, depending on its membrane remodeling capacity [15,21].…”

Section: Introductionmentioning

confidence: 93%

The glycosylation deficiency of flavivirus NS1 attenuates virus replication through interfering with the formation of viral replication compartments

Huang,

Shi,

Fan

et al. 2024

J Biomed Sci

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Background Flavivirus is a challenge all over the world. The replication of flavivirus takes place within membranous replication compartments (RCs) derived from endoplasmic reticulum (ER). Flavivirus NS1 proteins have been proven essential for the formation of viral RCs by remodeling the ER. The glycosylation of flavivirus NS1 proteins is important for viral replication, yet the underlying mechanism remains unclear. Methods HeLa cells were used to visualize the ER remodeling effects induced by NS1 expression. ZIKV replicon luciferase assay was performed with BHK-21 cells. rZIKV was generated from BHK-21 cells and the plaque assay was done with Vero Cells. Liposome co-floating assay was performed with purified NS1 proteins from 293T cells. Results We found that the glycosylation of flavivirus NS1 contributes to its ER remodeling activity. Glycosylation deficiency of NS1, either through N-glycosylation sites mutations or tunicamycin treatment, compromises its ER remodeling activity and interferes with viral RCs formation. Disruption of NS1 glycosylation results in abnormal aggregation of NS1, rather than reducing its membrane-binding activity. Consequently, deficiency in NS1 glycosylation impairs virus replication. Conclusions In summary, our results highlight the significance of NS1 glycosylation in flavivirus replication and elucidate the underlying mechanism. This provides a new strategy for combating flavivirus infections.

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“…Unlike NS4A, NS4B is often used as a molecular target due to its role in flavivirus replication and in dampening the host's immune system [208]. NS4B is a multi-transmembrane protein located in the endoplasmic reticulum membrane, where it plays an important role in the formation of the DENV replication complex by binding with NS3 [209].…”

Section: Ns4a and Ns4b Targetingmentioning

confidence: 99%

Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview

Diani,

Lagni,

Lotti

et al. 2023

Microorganisms

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Flaviviruses cause numerous pathologies in humans across a broad clinical spectrum with potentially severe clinical manifestations, including hemorrhagic and neurological disorders. Among human flaviviruses, some viral proteins show high conservation and are good candidates as targets for drug design. From an epidemiological point of view, flaviviruses cause more than 400 million cases of infection worldwide each year. In particular, the Yellow Fever, dengue, West Nile, and Zika viruses have high morbidity and mortality—about an estimated 20,000 deaths per year. As they depend on human vectors, they have expanded their geographical range in recent years due to altered climatic and social conditions. Despite these epidemiological and clinical premises, there are limited antiviral treatments for these infections. In this review, we describe the major compounds that are currently under evaluation for the treatment of flavivirus infections and the challenges faced during clinical trials, outlining their mechanisms of action in order to present an overview of ongoing studies. According to our review, the absence of approved antivirals for flaviviruses led to in vitro and in vivo experiments aimed at identifying compounds that can interfere with one or more viral cycle steps. Still, the currently unavailability of approved antivirals poses a significant public health issue.

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Flavivirus NS4B protein: Structure, function, and antiviral discovery

Cited by 16 publications

References 105 publications

The replication properties of a contemporary Zika virus from West Africa depends on NS1/NS4B proteins

The replication properties of a contemporary Zika virus from West Africa depends on NS1/NS4B proteins

The glycosylation deficiency of flavivirus NS1 attenuates virus replication through interfering with the formation of viral replication compartments

Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview

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