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PubMed2026

Redox cycling of viral RNA polymerase controls picornavirus replication.

Picornaviruses, including foot-and-mouth disease virus (FMDV), enterovirus 71 (EV71) and encephalomyocarditis virus (EMCV), are important pathogens that cause fever, herpes, and myocarditis in humans and animals. The interplay between picornaviruses and their hosts remains enigmatic. Here we perform porcine genome-wide CRISPR/Cas9 screens and identify methionine sulfoxide reductase B3 (MSRB3) as an essential factor for FMDV. MSRB3 deficiency inhibits FMDV replication. Mechanistically, MSRB3 eliminates methionine oxidation of FMDV 3D polymerase and stabilizes its expression. Further studies show that radical SAM domain-containing protein 1 (RSAD1) catalyzes methionine oxidation of FMDV 3D polymerase and promotes its aggregation and subsequent degradation through the autophagy-lysosome pathway. Importantly, RSAD1-MSRB3-mediated redox modification also affects the stability of 3D polymerases of EV71 and EMCV, and regulates their infectivity and pathogenesis both in vitro and in vivo. Collectively, this study corroborates that RSAD1-MSRB3-mediated redox cycling of 3D polymerase plays a conserved function in modulating picornavirus infection, providing insights into viral pathogenesis and broad-spectrum antiviral development.

Animals↗

PubMed2005

Factors required for the Uridylylation of the foot-and-mouth disease virus 3B1, 3B2, and 3B3 peptides by the RNA-dependent RNA polymerase (3Dpol) in vitro.

The 5' terminus of picornavirus genomic RNA is covalently linked to the virus-encoded peptide 3B (VPg). Foot-and-mouth disease virus (FMDV) is unique in encoding and using 3 distinct forms of this peptide. These peptides each act as primers for RNA synthesis by the virus-encoded RNA polymerase 3D(pol). To act as the primer for positive-strand RNA synthesis, the 3B peptides have to be uridylylated to form VPgpU(pU). For certain picornaviruses, it has been shown that this reaction is achieved by the 3D(pol) in the presence of the 3CD precursor plus an internal RNA sequence termed a cis-acting replication element (cre). The FMDV cre has been identified previously to be within the 5' untranslated region, whereas all other picornavirus cre structures are within the viral coding region. The requirements for the in vitro uridylylation of each of the FMDV 3B peptides has now been determined, and the role of the FMDV cre (also known as the 3B-uridylylation site, or bus) in this reaction has been analyzed. The poly(A) tail does not act as a significant template for FMDV 3B uridylylation.

Enhancer Elements, Genetic↗

PubMed2025

Metagenomic analysis of viral diversity in Portuguese bats.

Bats are highly diverse mammals and known reservoirs of numerous zoonotic viruses. Their role in the ecology of emerging infectious diseases continues to be of significant interest. This study aimed to evaluate the occurrence of coronaviruses (CoVs) in Portuguese bats and predict the affinity of their spike proteins with the aminopeptidase N (APN) receptor of several host species. The study also explored the viral diversity in bat samples using metagenomic sequencing. Ten bats (five Myotis myotis and five Miniopterus schreibersii) were captured at an underground roost in 2022 (Central Portugal), and fecal samples, oral, and anal swabs were collected (n = 27). A Pan-CoV nested RT-PCR was used for initial screening, followed by viral metagenomic sequencing of all fecal samples and one CoV-positive buccal swab. In silico protein docking studies were performed between a Portuguese bat CoV spike protein and APNs of bats, pigs, and humans. Pan-CoV nested RT-PCR identified three positive samples: two fecal samples and one buccal sample. Metagenomic sequencing allowed us to determine two near complete CoV genomes. Protein docking predicted strong binding of this spike protein to bat, porcine, and human APN receptors. Metagenomics also identified picornaviruses, adenovirus, and dependoparvovirus in fecal samples. This study reports the first near complete genome sequences of two members of the Alphacoronavirus genus from a Portuguese bat The identification of other viral families highlights the diverse virome of these cave-dwelling bat species. Protein docking studies suggest a potential for cross-species transmission of this bat CoV between bats, porcines and humans, though further research is needed to confirm these interactions.

Animals↗

PubMed2026

Selection profiles in RNA viruses reflect the characteristics of viruses more than individual proteins.

Proteins that are exposed on the surface of a virus are frequently subject to strong selection to escape from neutralizing antibodies. To investigate whether surface-exposed (SE) and non-exposed (NE) proteins encoded by RNA viruses exhibit different patterns of evolution under selection, we analyzed 244 protein-coding genes from 28 species of RNA viruses representing 15 taxonomic families. First, we show that gene-wide rates of non-synonymous (dN) and synonymous (dS) substitutions do not differentiate between SE and NE proteins. To incorporate variation in substitution rates among codon sites, we inferred the posterior distribution over a fixed grid of dN and dS rates for each alignment. This 'evolutionary fingerprint' provides a common framework for comparing the selection profiles of non-homologous genes. Next, we computed the Wasserstein distance for every pair of fingerprints, which is analogous to amount of work required to reshape one distribution to another. After compensating for differences in genetic variation among alignments, we found a small but significant difference between the fingerprints of SE and NE proteins (PERMANOVA, P = 0.03). However, we observed larger and more significant effects of whether the virus is enveloped (P < 10-5) and the interaction between these factors (P=6.9×10-4). The latter effects were driven by high levels of purifying selection in capsid proteins of Picornaviruses. Furthermore, greater amounts of variation in fingerprints were explained by significant differences among virus families and modes of transmission (P < 10-5). These results imply the pattern of selection on a virus protein is shaped more by characteristics of the virus than the protein itself.

RNA Viruses↗

PubMed2026

PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.

Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.

Polypyrimidine Tract-Binding Protein↗

PubMed2026

Crystal structures of Parechovirus A1 3Dpol reveal a mechanism of conformational stabilization in +ssRNA virus RNA-dependent RNA polymerase.

Parechovirus A1 (PeV A1) 3Dpol is an RNA-dependent RNA polymerase responsible for replication of the virus genome. We solved crystal structures of PeV A1 3Dpol structure in complex with GTP and in apo-state at 1.8-2.0 Å resolutions. In the 3Dpol-GTP complex, the conformation of the conserved motif B loop was stabilized by zinc ion coordination by cysteine residues. Apo-state structures of PeV A1 3Dpol showed significant conformational flexibility in the motif B loop, in the absence of zinc. While one of the conformational states of apo-3Dpol was similar to the 3Dpol-GTP complex structure, the alternative apo-3Dpol conformation showed a 4.3 Å movement of the motif B loop out of the active site cavity relative to the complex of 3Dpol with GTP. We propose that PeV A1 3Dpol activity is regulated by conformational stabilization of the motif B loop by zinc coordination.

Crystal structure↗

PubMed2026

A protein-dependent riboswitch activates ribosomal frameshifting in cardioviruses.

Programmed -1 ribosomal frameshifting (PRF) is a translational control mechanism used by RNA viruses to regulate the relative abundance of proteins encoded in different reading frames. Cardioviruses exhibit the highest known PRF efficiency, with ∼85% of ribosomes shifting into the -1 frame. This unusual event requires an interaction between the viral 2A protein and a stimulatory element in the RNA genome, but the basis for protein dependence is unclear. To address this, here we investigate the structure and dynamics of the PRF signal in Theiler's murine encephalitis virus (TMEV). By combining X-ray crystallography, small-angle X-ray scattering (SAXS), and single-molecule fluorescence resonance energy transfer (smFRET), we show that 2A binding switches the RNA from a stem-loop conformation into a pseudoknot, and we demonstrate that pseudoknot formation is essential for efficient PRF in vitro and in cells. Together, these findings illustrate how the cardiovirus PRF element behaves as a protein-dependent riboswitch, defining the molecular mechanism by which frameshifting is conditionally activated.

Frameshifting, Ribosomal↗