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Immunity Apr 2018Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn was required for the host...
Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory. Mn also enhanced STING activity by augmenting cGAMP-STING binding affinity. Mn-deficient mice showed diminished cytokine production and were more vulnerable to DNA viruses, and Mn-deficient STING-deficient mice showed no increased susceptibility. These findings indicate that Mn is critically involved and required for the host defense against DNA viruses.
Topics: Adult; Animals; Cell Line; Cricetinae; DNA Virus Infections; DNA Viruses; DNA, Viral; Enzyme Activation; Female; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions; Humans; Immunity, Innate; Male; Manganese; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nucleotidyltransferases; Young Adult
PubMed: 29653696
DOI: 10.1016/j.immuni.2018.03.017 -
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 -
Virology May 2015Virus genomes are condensed and packaged inside stable proteinaceous capsids that serve to protect them during transit from one cell or host organism, to the next.... (Review)
Review
Virus genomes are condensed and packaged inside stable proteinaceous capsids that serve to protect them during transit from one cell or host organism, to the next. During virus entry, capsid shells are primed and disassembled in a complex, tightly-regulated, multi-step process termed uncoating. Here we compare the uncoating-programs of DNA viruses of the pox-, herpes-, adeno-, polyoma-, and papillomavirus families. Highlighting the chemical and mechanical cues virus capsids respond to, we review the conformational changes that occur during stepwise disassembly of virus capsids and how these culminate in the release of viral genomes at the right time and cellular location to assure successful replication.
Topics: Capsid Proteins; DNA Viruses; DNA, Viral; Virus Uncoating
PubMed: 25728300
DOI: 10.1016/j.virol.2015.01.024 -
Journal of Clinical Oncology : Official... Nov 2017Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related...
Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation.
Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.
Topics: Adenoviruses, Human; Adult; BK Virus; DNA Virus Infections; DNA Viruses; Female; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Herpesvirus 6, Human; Humans; Immunotherapy, Adoptive; Male; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome
PubMed: 28783452
DOI: 10.1200/JCO.2017.73.0655 -
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 -
Nature Reviews. Microbiology Nov 2017One of the most prominent features of archaea is the extraordinary diversity of their DNA viruses. Many archaeal viruses differ substantially in morphology from... (Review)
Review
One of the most prominent features of archaea is the extraordinary diversity of their DNA viruses. Many archaeal viruses differ substantially in morphology from bacterial and eukaryotic viruses and represent unique virus families. The distinct nature of archaeal viruses also extends to the gene composition and architectures of their genomes and the properties of the proteins that they encode. Environmental research has revealed prominent roles of archaeal viruses in influencing microbial communities in ocean ecosystems, and recent metagenomic studies have uncovered new groups of archaeal viruses that infect extremophiles and mesophiles in diverse habitats. In this Review, we summarize recent advances in our understanding of the genomic and morphological diversity of archaeal viruses and the molecular biology of their life cycles and virus-host interactions, including interactions with archaeal CRISPR-Cas systems. We also examine the potential origins and evolution of archaeal viruses and discuss their place in the global virosphere.
Topics: Archaea; Archaeal Viruses; DNA Viruses; Genetic Variation; Genome, Viral
PubMed: 29123227
DOI: 10.1038/nrmicro.2017.125 -
Annual Review of Virology Sep 2018Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of... (Review)
Review
Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of viruses and how they interact with cellular processes have historically provided seminal insights into basic biology and disease mechanisms. The replicative life cycles of many DNA viruses have been shown to engage components of the host DNA damage and repair machinery. Viruses have evolved numerous strategies to navigate the cellular DNA damage response. By hijacking and manipulating cellular replication and repair processes, DNA viruses can selectively harness or abrogate distinct components of the cellular machinery to complete their life cycles. Here, we highlight consequences for viral replication and host genome integrity during the dynamic interactions between virus and host.
Topics: DNA Damage; DNA Repair; DNA Replication; DNA Viruses; DNA, Viral; Virus Replication
PubMed: 29996066
DOI: 10.1146/annurev-virology-092917-043534 -
Nature Mar 2024Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis...
Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2'3'-cyclic GMP-AMP (cGAMP). The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin-RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation.
Topics: Animals; Humans; Mice; Cell Nucleus; Cryoelectron Microscopy; Degrons; DNA Virus Infections; DNA Viruses; DNA, Viral; Immunity, Innate; Innate Immunity Recognition; Interferon Type I; Nuclear Proteins; Nucleosomes; Nucleotidyltransferases; Proteasome Endopeptidase Complex; Protein Stability; Proteolysis; Substrate Specificity; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 38418882
DOI: 10.1038/s41586-024-07112-w -
Journal of Molecular Biology Jun 2023Viruses infect all kingdoms of life; their genomes vary from DNA to RNA and in size from 2kB to 1 MB or more. Viruses frequently employ disordered proteins, that is,... (Review)
Review
Viruses infect all kingdoms of life; their genomes vary from DNA to RNA and in size from 2kB to 1 MB or more. Viruses frequently employ disordered proteins, that is, protein products of virus genes that do not themselves fold into independent three-dimensional structures, but rather, constitute a versatile molecular toolkit to accomplish a range of functions necessary for viral infection, assembly, and proliferation. Interestingly, disordered proteins have been discovered in almost all viruses so far studied, whether the viral genome consists of DNA or RNA, and whatever the configuration of the viral capsid or other outer covering. In this review, I present a wide-ranging set of stories illustrating the range of functions of IDPs in viruses. The field is rapidly expanding, and I have not tried to include everything. What is included is meant to be a survey of the variety of tasks that viruses accomplish using disordered proteins.
Topics: Intrinsically Disordered Proteins; RNA Viruses; DNA Viruses; Genome, Viral; RNA, Viral; DNA, Viral
PubMed: 37330280
DOI: 10.1016/j.jmb.2022.167860