RNA Binding Proteins as Pioneer Determinants of Infection: Protective, Proviral, or Both?

Lisy, Samantha M.; Rothamel, Katherine; Ascano, Manuel

doi:10.3390/v13112172

Cited by 18 publications

(10 citation statements)

References 191 publications

(349 reference statements)

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“…Cellular RNA-binding proteins have been extensively studied in the context of viral infection, for viruses with both DNA and RNA genomes (Lisy et. al., 2021).…”

Section: Discussionmentioning

confidence: 99%

Nucleolin-RNA interaction modulates rotavirus replication

Hernández-Guzmán,

Arias,

López

et al. 2023

Preprint

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Rotavirus infection is a leading cause of gastroenteritis in children worldwide, the genome of this virus is composed of eleven segments of dsRNA packed in a triple-layered protein capsid. Here, we investigated the role of nucleolin, a protein with diverse RNA-binding domains, on rotavirus infection. Knocking down the expression of nucleolin in MA104 cells by RNA interference resulted in a remarkable 5-fold increase in the production of infectious rhesus rotavirus (RRV) progeny, accompanied by an elevated synthesis of viral mRNA and genome copies. Further analysis unveiled an interaction between rotavirus segment 10 (S10) and nucleolin, potentially mediated by G-quadruplex domains on the viral genome. To determine whether the nucleolin-RNA interaction regulates RRV replication, MA104 cells were transfected with AGRO100, a compound that forms G4 structures and selectively inhibits nucleolin-RNA interactions by blocking the RNA binding domains. Under these conditions, viral production increased by 1.54-fold, indicating the inhibitory role of nucleolin on the yield of infectious viral particles. Furthermore, G4 sequences were identified in all eleven RRV dsRNA segments, and transfection of oligonucleotides representing G4 sequences in RRV S10 induced a significant increase in viral production. These findings show that rotavirus replication is negatively regulated by nucleolin through direct interaction with the viral RNAs by sequences forming G4 structures.ImportanceViruses rely on cellular proteins to carry on their replicative cycle. In the case of rotavirus, the involvement of cellular RNA-binding proteins during the replicative cycle is a poorly studied field. In this work, we demonstrate for the first time the interaction between nucleolin and viral RNA of rotavirus RRV. Nucleolin is a cellular protein that has a role in the metabolism of ribosomal rRNA, and ribosome biogenesis, which seems to have regulatory effects on the quantity of viral particles and viral RNA copies of rotavirus RRV. Our study adds a new component to the current model of rotavirus replication, where cellular proteins can have a negative regulation on rotavirus replication.

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“…Cellular RNA-binding proteins have been extensively studied in the context of viral infection, for viruses with both DNA and RNA genomes (Lisy et. al., 2021).…”

Section: Discussionmentioning

confidence: 99%

Nucleolin-RNA interaction modulates rotavirus replication

Hernández-Guzmán,

Arias,

López

et al. 2023

Preprint

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“…This suggests that the fundamental role of Grx2 is to maintain redox homeostasis in the organism. In addition, RBM28 is an intracellular host factor that can interact directly with RNA viruses [ 19 ]. ISOC1 is involved in intracellular pathogen recognition and clearance [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Expression Analysis of a Novel Oxidoreductase Glutaredoxin 2 in Black Tiger Shrimp, Penaeus monodon

Fan

Yang

et al. 2022

Antioxidants

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Glutaredoxin (Grx) is a glutathione-dependent oxidoreductase that is an important component of the redox system in organisms. However, there is a serious lack of sequence information and functional validation related to Grx in crustaceans. In this study, a novel Grx was identified in Penaeus monodon (PmGrx2). The full-length cDNA of PmGrx2 is 998 bp, with an open reading frame (ORF) of 441 bp, encoding 119 amino acids. Sequence alignment showed that PmGrx2 had the highest identity with Grx2 of Penaeus vannamei at 96.64% and clustered with Grx2 of other crustaceans. Quantitative real-time PCR (qRT-PCR) analysis showed that PmGrx2 was expressed in all examined tissues, with higher expression levels in the stomach and testis. PmGrx2 was continuously expressed during development and had the highest expression level in the zygote stage. Both ammonia-N stress and bacterial infection could differentially induce the expression of PmGrx2 in hepatopancreas and gills. When PmGrx2 was inhibited, the expression of antioxidant enzymes was suppressed, the degree of apoptosis increased, and the GSH content decreased with the prolongation of ammonia-N stress. Inhibition of PmGrx2 resulted in shrimp being exposed to a greater risk of oxidative damage. In addition, an SNP locus was screened on the exons of PmGrx2 that was significantly associated with an ammonia-N-stress-tolerance trait. This study suggests that PmGrx2 is involved in redox regulation and plays an important role in shrimps’ resistance to marine environmental stresses.

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“…In particular, viral infections can trigger a cellular DNA damage response (DDR), due to the recognition of viral genomes, which can prevent their replication (Weitzman and Fradet-Turcotte, 2018;Lopez et al, 2022). Cellular RNA binding proteins (RBPs), participating at all steps of RNA metabolism, may be also engaged in a conflictual relationship with viral replication (Garcia-Moreno et al, 2018;Girardi et al, 2021;Lisy et al, 2021). In addition, cells can mount an innate response, intimately linked to the intrinsic one, resulting in the production of interferons or inflammatory cytokines which further amplify the anti-viral effect of both infected and neighboring cells (Guillemin et al, 2021;Justice and Cristea, 2022;Lopez et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

Pastor,

Charles,

Belmudes

et al. 2024

Preprint

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Phosphorylation is a major post-translation modification (PTM) of proteins, and small molecules, which is finely tuned by the activity of several hundred kinases and phosphatases. It controls most if not all cellular pathways including anti-viral responses. Accordingly, viruses often induce important changes in the phosphorylation of host factors that can either help or counteract viral replication. Among more than 500 kinases constituting the human kinome only few have been described as important for the Hepatitis B virus (HBV) infectious cycle, and most of them intervene during early or late infectious steps by phosphorylating the viral Core protein (HBc) protein. In addition, scarce information is available on the consequences of HBV infection on the activity of cellular kinases. The objective of this study was to investigate the global impact of HBV infection on the cellular phosphorylation landscape at early after infection. For this, primary human hepatocytes (PHH) were challenged or not with HBV, and a mass spectrometry (MS)-based quantitative phosphoproteomic analysis was conducted two- and seven-days post-infection. The results indicated that while, as expected, HBV infection only minimally modified the cell proteome, important changes were observed on the phosphorylation level of several host proteins at both times points. Gene enrichment and ontology analyses of up- and down- phosphorylated proteins revealed common and distinct signatures induced following infection. In particular, HBV infection resulted in up-phosphorylation of proteins involved in DNA damage signaling and repair, RNA metabolism, in particular splicing, and cytoplasmic cell-signaling. Several down-phosphorylated factors, mostly involved in cell signaling and communication, were also detected. Validation studies performed on some selected up-phosphorylated proteins, revealed that HBV infection induced a DNA damage response characterized by the appearance of 53BP1 foci, whose siRNA-mediated knock-down increased cccDNA levels. In addition, among up-phosphorylated RBPs, SRRM2, a major scaffold of nuclear speckles behaved as antiviral factor. In accordance with these findings, kinase prediction analysis indicated that HBV infection upregulates the activity of major kinases involved in DNA repair. These results strongly suggest that HBV infection triggers an intrinsic anti-viral response composed by DNA repair factors and RBPs that contribute to reduce HBV replication in cell culture models.

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RNA Binding Proteins as Pioneer Determinants of Infection: Protective, Proviral, or Both?

Cited by 18 publications

References 191 publications

Nucleolin-RNA interaction modulates rotavirus replication

Nucleolin-RNA interaction modulates rotavirus replication

Expression Analysis of a Novel Oxidoreductase Glutaredoxin 2 in Black Tiger Shrimp, Penaeus monodon

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

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