Human DDX3X Unwinds Japanese Encephalitis and Zika Viral 5′ Terminal Regions

Nelson, Corey R; Mrozowich, Tyler; Gemmill, Darren L.; Park, Sean M; Patel, Trushar R.

doi:10.3390/ijms22010413

Cited by 17 publications

(15 citation statements)

References 81 publications

(54 reference statements)

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“…The regulation of the prionoid transition of NLRP3 inflammasome into supramolecular complexes is mediated by DEAD-box helicase 3 (DDX3X or DDX3)—a host X-chromosome encoded DEAD-box RNA helicase that is often hijacked by SARS-CoV-2 and other viruses [ 514 , 515 ]. In total, 18 species of virus from 12 genera—including the dengue virus [ 516 ], HIV-1 virus [ 517 , 518 ], hepatitis C virus [ 519 ], Japanese Encephalitis virus, and the Zika virus [ 520 ]—have been determined to be dependent upon DDX3X for virulence [ 521 ]. The ATP-bound form of DDX3X is necessary for the scaffolding of the ASC domain to transition into irreversible, stable, and insoluble supramolecular prionoid-like assemblies [ 494 ].…”

Section: Melatonin Protects Mitochondria and Atp Production To Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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Section: Melatonin Protects Mitochondria and Atp Production To Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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“…West Nile virus (WNV) is a flavivirus that hijacks DDX3 from P-bodies to cytoplasmic sites of viral replication, altering the assembly of these membraneless organelles while promoting viral replication [71]. In the case of Japanese encephalitis virus (JEV), DDX3 was shown to favor viral replication through the binding to the 5 -UTR of the viral genome and to viral proteins NS3 and NS5 [72]. More recently, DDX3 was shown to unwind the 5 -UTR of the viral genome suggesting that the cellular RNA helicase facilitates viral RNA translation and consequently viral replication [73].…”

Section: Flaviviruses and Hepacivirusmentioning

confidence: 99%

RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling

2021

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DDX3 is a cellular ATP-dependent RNA helicase involved in different aspects of RNA metabolism ranging from transcription to translation and therefore, DDX3 participates in the regulation of key cellular processes including cell cycle progression, apoptosis, cancer and the antiviral immune response leading to type-I interferon production. DDX3 has also been described as an essential cellular factor for the replication of different viruses, including important human threats such HIV-1 or HCV, and different small molecules targeting DDX3 activity have been developed. Indeed, increasing evidence suggests that DDX3 can be considered not only a promising but also a viable target for anticancer and antiviral treatments. In this review, we summarize distinct functional aspects of DDX3 focusing on its participation as a double-edged sword in the host immune response and in the replication cycle of different viruses.

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“…JEV viral non-coding RNAs were purified immediately after in vitro transcription using SEC, similar to previous works (16,38,39). The elution profile for JEV 5’TR (Figure 3A) indicates that the RNA elutes at approximately 11.5 mL as a single monodispersed species, evident by the typical Gaussian distribution.…”

Section: Resultsmentioning

confidence: 99%

Investigating RNA-RNA interactions through computational and biophysical analysis

Mrozowich

Park

Waldl

et al. 2022

Preprint

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Many flaviviruses such as Dengue and West Nile virus undergo essential long-range interactions of their 5' and 3' terminal regions (TRs), mediated by a conserved complementary cyclization sequence. However, we lack insights into such long-range interactions for the Japanese Encephalitis virus (JEV). Here, we utilized an extensive, multi-faceted approach involving computational and biophysical tools. We performed multi-angle light scattering (SEC-MALS) to determine absolute molecular weights of JEV TRs, and their complex concluding they form a 1:1 complex and corroborated this interaction using analytical ultracentrifugation (AUC). The microscale thermophoresis (MST) experiments demonstrated that the 5' and 3' TR of JEV interact with nM affinity, which is significantly reduced without the conserved cyclization sequence. To our knowlwege, this is the first study representing the application of three key biophysical methods (AUC, MST and SEC-MALS) to study RNA-RNA interactions. Furthermore, we performed computational kinetic analyses corroborating our MST studies showing the essential role of the cyclization sequence in the RNA-RNA interaction. The binding affinity of this biologically critical event is a vital pharmacological feature that can influence potential competitive inhibition by therapeutics. This evidence can also influence pharmaceutical interventions aimed at inhibiting the conserved flavivirus cyclization, thus, interrupting replication across the flavivirus family.

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Human DDX3X Unwinds Japanese Encephalitis and Zika Viral 5′ Terminal Regions

Cited by 17 publications

References 81 publications

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling

Investigating RNA-RNA interactions through computational and biophysical analysis

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