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Science (New York, N.Y.) Nov 2019African swine fever virus (ASFV) is a giant and complex DNA virus that causes a highly contagious and often lethal swine disease for which no vaccine is available. Using...
African swine fever virus (ASFV) is a giant and complex DNA virus that causes a highly contagious and often lethal swine disease for which no vaccine is available. Using an optimized image reconstruction strategy, we solved the ASFV capsid structure up to 4.1 angstroms, which is built from 17,280 proteins, including one major (p72) and four minor (M1249L, p17, p49, and H240R) capsid proteins organized into pentasymmetrons and trisymmetrons. The atomic structure of the p72 protein informs putative conformational epitopes, distinguishing ASFV from other nucleocytoplasmic large DNA viruses. The minor capsid proteins form a complicated network below the outer capsid shell, stabilizing the capsid by holding adjacent capsomers together. Acting as core organizers, 100-nanometer-long M1249L proteins run along each edge of the trisymmetrons that bridge two neighboring pentasymmetrons and form extensive intermolecular networks with other capsid proteins, driving the formation of the capsid framework. These structural details unveil the basis of capsid stability and assembly, opening up new avenues for African swine fever vaccine development.
Topics: African Swine Fever Virus; Animals; Capsid; Capsid Proteins; Cells, Cultured; Cryoelectron Microscopy; Epitopes; Models, Molecular; Protein Conformation; Protein Domains; Protein Folding; Protein Structure, Secondary; Swine; Virion; Virus Assembly
PubMed: 31624094
DOI: 10.1126/science.aaz1439 -
Microbiology and Molecular Biology... May 2020Viruses and mobile genetic elements are molecular parasites or symbionts that coevolve with nearly all forms of cellular life. The route of virus replication and protein... (Review)
Review
Viruses and mobile genetic elements are molecular parasites or symbionts that coevolve with nearly all forms of cellular life. The route of virus replication and protein expression is determined by the viral genome type. Comparison of these routes led to the classification of viruses into seven "Baltimore classes" (BCs) that define the major features of virus reproduction. However, recent phylogenomic studies identified multiple evolutionary connections among viruses within each of the BCs as well as between different classes. Due to the modular organization of virus genomes, these relationships defy simple representation as lines of descent but rather form complex networks. Phylogenetic analyses of virus hallmark genes combined with analyses of gene-sharing networks show that replication modules of five BCs (three classes of RNA viruses and two classes of reverse-transcribing viruses) evolved from a common ancestor that encoded an RNA-directed RNA polymerase or a reverse transcriptase. Bona fide viruses evolved from this ancestor on multiple, independent occasions via the recruitment of distinct cellular proteins as capsid subunits and other structural components of virions. The single-stranded DNA (ssDNA) viruses are a polyphyletic class, with different groups evolving by recombination between rolling-circle-replicating plasmids, which contributed the replication protein, and positive-sense RNA viruses, which contributed the capsid protein. The double-stranded DNA (dsDNA) viruses are distributed among several large monophyletic groups and arose via the combination of distinct structural modules with equally diverse replication modules. Phylogenomic analyses reveal the finer structure of evolutionary connections among RNA viruses and reverse-transcribing viruses, ssDNA viruses, and large subsets of dsDNA viruses. Taken together, these analyses allow us to outline the global organization of the virus world. Here, we describe the key aspects of this organization and propose a comprehensive hierarchical taxonomy of viruses.
Topics: DNA Replication; DNA Viruses; Evolution, Molecular; Genes, Viral; Genome, Viral; Phylogeny; RNA Viruses; Virus Physiological Phenomena; Viruses
PubMed: 32132243
DOI: 10.1128/MMBR.00061-19 -
Biomolecules Jul 2022Although traditionally viewed as streamlined and simple, discoveries over the last century have revealed that viruses can exhibit surprisingly complex physical... (Review)
Review
Although traditionally viewed as streamlined and simple, discoveries over the last century have revealed that viruses can exhibit surprisingly complex physical structures, genomic organization, ecological interactions, and evolutionary histories. Viruses can have physical dimensions and genome lengths that exceed many cellular lineages, and their infection strategies can involve a remarkable level of physiological remodeling of their host cells. Virus-virus communication and widespread forms of hyperparasitism have been shown to be common in the virosphere, demonstrating that dynamic ecological interactions often shape their success. And the evolutionary histories of viruses are often fraught with complexities, with chimeric genomes including genes derived from numerous distinct sources or evolved de novo. Here we will discuss many aspects of this viral complexity, with particular emphasis on large DNA viruses, and provide an outlook for future research.
Topics: Biological Evolution; DNA Viruses; Genome, Viral; Genomics; Phylogeny; Viruses
PubMed: 36008955
DOI: 10.3390/biom12081061 -
Viruses Feb 2021The APOBEC family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved... (Review)
Review
The APOBEC family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes - APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new host-pathogen conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.
Topics: APOBEC Deaminases; Animals; DNA Replication; DNA Viruses; DNA, Viral; Herpesviridae; Herpesviridae Infections; Host-Pathogen Interactions; Humans; Virus Replication
PubMed: 33671095
DOI: 10.3390/v13030390 -
The Journal of Biological Chemistry Apr 2020The WW domain is a modular protein structure that recognizes the proline-rich Pro-Pro-x-Tyr (PPxY) motif contained in specific target proteins. The compact modular... (Review)
Review
The WW domain is a modular protein structure that recognizes the proline-rich Pro-Pro-x-Tyr (PPxY) motif contained in specific target proteins. The compact modular nature of the WW domain makes it ideal for mediating interactions between proteins in complex networks and signaling pathways of the cell ( the Hippo pathway). As a result, WW domains play key roles in a plethora of both normal and disease processes. Intriguingly, RNA and DNA viruses have evolved strategies to hijack cellular WW domain-containing proteins and thereby exploit the modular functions of these host proteins for various steps of the virus life cycle, including entry, replication, and egress. In this review, we summarize key findings in this rapidly expanding field, in which new virus-host interactions continue to be identified. Further unraveling of the molecular aspects of these crucial virus-host interactions will continue to enhance our fundamental understanding of the biology and pathogenesis of these viruses. We anticipate that additional insights into these interactions will help support strategies to develop a new class of small-molecule inhibitors of viral PPxY-host WW-domain interactions that could be used as antiviral therapeutics.
Topics: Amino Acid Motifs; DNA Viruses; Host-Pathogen Interactions; Humans; RNA Viruses; Ubiquitin-Protein Ligases; Viral Matrix Proteins; Virus Internalization; Viruses; WW Domains
PubMed: 32111739
DOI: 10.1074/jbc.REV119.012414 -
Cold Spring Harbor Perspectives in... Aug 2021Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and... (Review)
Review
Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and therefore transverse the nuclear envelope barrier through the nuclear pore complex. Viral genomes then become chromatinized either in their episomal form or upon integration into the host genome. Interactions with host DNA, transcription factors or nuclear bodies mediate their replication. Often interfering with nuclear functions, viruses use nuclear architecture to ensure persistent infections. Discovering these multiple modes of replication and persistence served in unraveling many important nuclear processes, such as nuclear trafficking, transcription, and splicing. Here, by using examples of DNA and RNA viral families, we portray the nucleus with the virus inside.
Topics: Animals; Cell Nucleus; DNA Viruses; Gene Expression Regulation, Viral; Humans; RNA Viruses; Virus Integration
PubMed: 33753405
DOI: 10.1101/cshperspect.a039446 -
Viruses Aug 2021The apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzyme family in humans has 11 members with diverse functions in metabolism and immunity [...].
The apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzyme family in humans has 11 members with diverse functions in metabolism and immunity [...].
Topics: APOBEC-1 Deaminase; Animals; DNA Viruses; Humans; Immunity, Innate; Mice; RNA Editing
PubMed: 34452478
DOI: 10.3390/v13081613 -
Journal of Molecular Biology Aug 2023An emerging set of results suggests that liquid-liquid phase separation (LLPS) is the basis for the formation of membrane-less compartments in cells. Evidence is now... (Review)
Review
An emerging set of results suggests that liquid-liquid phase separation (LLPS) is the basis for the formation of membrane-less compartments in cells. Evidence is now mounting that various types of virus-induced membrane-less compartments and organelles are also assembled via LLPS. Specifically, viruses appear to use intracellular phase transitions to form subcellular microenvironments known as viral factories, inclusion bodies, or viroplasms. These compartments - collectively referred to as viral biomolecular condensates - can be used to concentrate replicase proteins, viral genomes, and host proteins that are required for virus replication. They can also be used to subvert or avoid the intracellular immune response. This review examines how certain DNA or RNA viruses drive the formation of viral condensates, the possible biological functions of those condensates, and the biophysical and biochemical basis for their assembly.
Topics: RNA Viruses; Virus Replication; DNA Viruses; Phase Transition; Biomolecular Condensates
PubMed: 36642156
DOI: 10.1016/j.jmb.2023.167955 -
Current Opinion in Virology Oct 2022Poxviruses are large double-stranded DNA viruses that encode their own DNA replication, transcription, and mRNA biogenesis machinery, which underlies their ability to... (Review)
Review
Poxviruses are large double-stranded DNA viruses that encode their own DNA replication, transcription, and mRNA biogenesis machinery, which underlies their ability to replicate entirely in the cytoplasm. However, like all other viruses, poxviruses remain dependent on host ribosomes to translate their mRNAs into the viral proteins needed to complete their replication cycle. While earlier studies established a fundamental understanding of how poxviruses wrestle with their hosts for control of translation initiation and elongation factors that guide ribosome recruitment and mRNA decoding, recent work has begun to reveal the extent to which poxviruses directly target the ribosome itself. This review summarizes our current understanding of the regulation of ribosomes and translation in poxvirus infection.
Topics: Humans; Vaccinia virus; Ribosomes; Poxviridae; Poxviridae Infections; RNA, Messenger; Virus Replication
PubMed: 36270183
DOI: 10.1016/j.coviro.2022.101256 -
Cellular & Molecular Biology Letters Oct 2023N-methyladenosine (mA) modification is a dynamic, reversible process and is the most prevalent internal modification of RNA. This modification is regulated by three... (Review)
Review
N-methyladenosine (mA) modification is a dynamic, reversible process and is the most prevalent internal modification of RNA. This modification is regulated by three protein groups: methyltransferases ("writers"), demethylases ("erasers"), and mA-binding proteins ("readers"). mA modification and related enzymes could represent an optimal strategy to deepen the epigenetic mechanism. Numerous reports have suggested that aberrant modifications of mA lead to aberrant expression of important viral genes. Here, we review the role of mA modifications in viral replication and virus-host interactions. In particular, we focus on DNA and RNA viruses associated with human diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV)-1, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). These findings will contribute to the understanding of the mechanisms of virus-host interactions and the design of future therapeutic targets for treatment of tumors associated with viral infections.
Topics: Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Virus Diseases; Herpesvirus 8, Human; Virus Replication
PubMed: 37828480
DOI: 10.1186/s11658-023-00490-5