How Do Flaviviruses Hijack Host Cell Functions by Phase Separation?

Saito, Akatsuki; Shofa, Maya; Ode, Hirotaka; Yumiya, Maho; Hirano, Junko; Okamoto, Tomoyoshi; Yoshimura, Shige H.

doi:10.3390/v13081479

Cited by 13 publications

(9 citation statements)

References 134 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased cell complexity in eukaryotes is correlated with a significantly higher level of disorder compared to prokaryotes [ 202 ], implying the lack of an ordered, three-dimensional structure confers higher flexibility in protein–protein interactions that are instrumental in cell signaling and molecular communication [ 203 , 204 , 205 ]. Viruses employ several successful tactics to hijack and control host biomolecular condensates by utilizing the unique features of IDRs in their proteins to accomplish this task [ 206 ]. Consequently, IDRs in viruses are often associated with viral infectivity and pathogenicity [ 207 ].…”

Section: Sars-cov-2 Proteins Phase Separation Disrupt Host Biomolecul...mentioning

confidence: 99%

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

Loh¹,

Reíter

2022

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Sars-cov-2 Proteins Phase Separation Disrupt Host Biomolecul...mentioning

confidence: 99%

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

Loh¹,

Reíter

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…The secondary structure of proteins, particularly IDRs play decisive mechanistic roles in phase separation ( 16 , 32 , 33 ). To assess if IDRs were responsible for the formation of the condensates observed with NS2–RNA complexes, we monitored changes in the secondary structure of 5.4 μM NS2 with increasing concentrations (from 0.02 to 0 0.46 μM) of S10 RNA by circular dichroism (CD).…”

Section: Resultsmentioning

confidence: 99%

Role of NS2 specific RNA binding and phosphorylation in liquid–liquid phase separation and virus assembly

Rahman

Ampah

Roy

2022

Nucleic Acids Research

View full text Add to dashboard Cite

Liquid–liquid phase separation (LLPS) has assumed a prominent role in biological cell systems, where it underpins the formation of subcellular compartments necessary for cell function. We investigated the underlying mechanism of LLPS in virus infected cells, where virus inclusion bodies are formed by an RNA-binding phosphoprotein (NS2) of Bluetongue virus to serve as sites for subviral particle assembly and virus maturation. We show that NS2 undergoes LLPS that is dependent on protein phosphorylation and RNA-binding and that LLPS occurrence is accompanied by a change in protein secondary structure. Site-directed mutagenesis identified two critical arginine residues in NS2 responsible for specific RNA binding and thus for NS2–RNA complex driven LLPS. Reverse genetics identified the same residues as essential for VIB assembly in infected cells and virus viability. Our findings suggest that a specific arginine–RNA interaction in the context of a phosphorylated state drives LLPS in this, and possibly other, virus infections.

show abstract

“…Phase separation studies of viral components show they can interact with host proteins to hijack host cell functions (Saito et al, 2021) or inhibit immune recognition by the host (e.g., Heinrich et al, 2018). Host DNA sensors are cytosolic (as are TSE infectious particles) and can respond to viral DNA and induce IFN-β (Nagarajan, 2011).…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Prion Protein With Increased Interferon-β Fail to Limit Creutzfeldt-Jakob Disease Agent Replication in Differentiating Neuronal Cells

2022

View full text Add to dashboard Cite

Immortalized uninfected septal (SEP) neurons proliferate but after physiological mitotic arrest they express differentiated neuronal characteristics including enhanced cell-to-cell membrane contacts and ≥ 8 fold increases in host prion protein (PrP). We compared proliferating uninfected and Creutzfeldt-Jakob Disease (CJD) agent infected cells with their arrested counterparts over 33 days by quantitative mRNA and protein blot analyses. Surprisingly, uninfected arrested cells increased interferon-β (IFN-β) mRNA by 2.5–8 fold; IFN-β mRNA elevations were not previously associated with neuronal differentiation. SEP cells with high CJD infectivity titers produced a much larger 40–68-fold increase in IFN-β mRNA, a classic host anti-viral response that is virucidal for RNA but not DNA viruses. High titers of CJD agent also induced dramatic decreases in host PrP, a protein needed for productive agent replication. Uninfected arrested cells produced large sustained 20–30-fold increases in PrP mRNA and protein, whereas CJD arrested cells showed only transient small 5-fold increases in PrP. A > 10-fold increase in infectivity, but not PrP misfolding, induced host PrP reductions that can limit CJD agent replication. In contrast to neuronal lineage cells, functionally distinct migratory microglia with high titers of CJD agent do not induce an IFN-β mRNA response. Because they have 1/50th of PrP of an average brain cell, microglia would be unable to produce the many new infectious particles needed to induce a large IFN-β response by host cells. Instead, microglia and related cells can be persistent reservoirs of infection and spread. Phase separations of agent-associated molecules in neurons, microglia and other cell types can yield new insights into the molecular structure, persistent, and evasive behavior of CJD-type agents.

show abstract

How Do Flaviviruses Hijack Host Cell Functions by Phase Separation?

Cited by 13 publications

References 134 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

Role of NS2 specific RNA binding and phosphorylation in liquid–liquid phase separation and virus assembly

Reduced Expression of Prion Protein With Increased Interferon-β Fail to Limit Creutzfeldt-Jakob Disease Agent Replication in Differentiating Neuronal Cells

Contact Info

Product

Resources

About