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Structure of a zinc-finger antiviral protein in complex with RNA reveals mechanism for selective targeting of CG-rich viral sequences

ABSTRACT: Structure of a zinc-finger antiviral protein in complex with RNA reveals mechanism for selective targeting of CG-rich viral sequences

PROVIDER: PRJNA586855 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10379741.fastq.gz	Fastqsanger.gz
	SRR10379742.fastq.gz	Fastqsanger.gz
	SRR10379743.fastq.gz	Fastqsanger.gz
	SRR10379744.fastq.gz	Fastqsanger.gz
	SRR10379745.fastq.gz	Fastqsanger.gz

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Similar Datasets

Structure of a zinc-finger antiviral protein in complex with RNA reveals mechanism for selective targeting of CG-rich viral sequences

Project description:Infection of animal cells by many viruses is detected and countered by a variety of means, including recognition of non-self nucleic acids. The zinc-finger antiviral protein (ZAP) depletes cytoplasmic RNA that is recognized as foreign in mammalian cells by virtue of its elevated CG dinucleotide content compared to endogenous mRNAs. Here, we determined a crystal structure of a protein-RNA complex containing the N-terminal, four-zinc finger human (h) ZAP RNA binding domain (RBD), and a CG dinucleotide-containing RNA target. The structure reveals in molecular detail how hZAP is able to bind selectively to CG-rich RNA. Specifically, the four zinc fingers create a basic patch on the hZAP RBD surface. The highly basic second zinc finger contains a pocket that selectively accommodates CG dinucleotide bases. Structure guided mutagenesis, crosslinking-immunoprecipitation-sequencing assays, and RNA affinity assays show that the structurally defined CG-binding pocket is not required for RNA binding per se in human cells. However, the pocket is a crucial determinant of high affinity specific binding to CG-dinucleotide-containing RNA. Moreover, variations in the RNA binding specificity a panel of CG-binding pocket mutants quantitatively predict their selective antiviral activity against a CG-enriched HIV-1 strain. Overall, the hZAP RBD:RNA structure provides an atomic-level explanation for how ZAP selectively targets foreign, CG-rich RNA.

2019-11-01 | GSE139667 | GEO

The zinc finger antiviral protein ZAP destabilises viral transcripts and restricts human cytomegalovirus

Project description:Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonises several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is largely unknown. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, the long (ZAP-L) and short (ZAP-S), is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP decelerates the progression of HCMV infection. SLAM-sequencing revealed that ZAP restricts HCMV at early stages of infection by destabilising a distinct subset of viral transcripts with low CG content. In summary, this report provides evidence of an important antiviral role for ZAP in host defense against HCMV infection and highlights its differentiated function during DNA virus infection.

2021-04-22 | PXD023559 | Pride

CG-dinucleotide suppression enables antiviral defense targeting non-self RNA

Project description:Vertebrate genomes exhibit marked CG-suppression, that is lower than expected numbers of 5’-CG-3’ dinucleotides1. This feature is likely due to C-to-T mutations that have accumulated over hundreds of millions of years, driven by CG-specific DNA methyl transferases and spontaneous methyl-cytosine deamination. Remarkably, many RNA viruses of vertebrates that are not substrates for DNA methyl transferases mimic the CG-suppression of their hosts2-4. This striking property of viral genomes is unexplained4-6. In a synonymous mutagenesis experiment, we found that CG-suppression is essential for HIV-1 replication. The deleterious effect of CG dinucleotides on HIV-1 replication was cumulative, evident as cytoplasmic RNA depletion, and exerted by CG dinucleotides in both translated and non-translated exonic RNA sequences. A focused siRNA screen revealed that zinc finger antiviral protein (ZAP)7 inhibited virion production by cells infected with CG-enriched HIV-1. Crucially, HIV-1 mutants containing segments whose CG-content mimicked random sequence were defective in unmanipulated cells, but replicated normally in ZAP-deficient cells. Crosslinking-immunoprecipitation-sequencing assays demonstrated that ZAP binds directly and selectively to RNA sequences containing CG dinucleotides. These findings suggest that ZAP exploits host CG-suppression to discriminate non-self RNA. The dinucleotide composition of HIV-1, and perhaps other RNA viruses, appears to have adapted to evade this host defense.

2017-08-22 | GSE102843 | GEO

Strain Dependent Restriction of Human Cytomegalovirus by Zinc Finger Antiviral Proteins

Project description:Strain Dependent Restriction of Human Cytomegalovirus by Zinc Finger Antiviral Proteins

| PRJEB58764 | ENA

RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

Project description:Synonymous recoding of viral genome can attenuate their replication, but can have pleiotropic effects, with multiple mechanisms contributing to attenuation. We set out to design recoded viral genomes whose attenuation was specific and conditional. The zinc finger antiviral protein (ZAP) recognizes CpG dinucleotides and targets CpG-rich RNAs for depletion, but RNA features such as CpG numbers, spacing and surrounding nucleotide composition that enable specific modulation by ZAP are undescribed. Using synonymously mutated HIV-1 genomes, we define several sequence features that govern ZAP sensitivity and stable attenuation. Using features defined using HIV-1, we then designed a mutant enterovirus A71 genome whose attenuation was also stable and strictly ZAP-dependent, both in cell culture and in mice. This conditionally attenuated enterovirus A71 elicited neutralizing antibodies that were protective against wild-type enterovirus 71 infection and disease. Elucidation of the determinants of ZAP sensitivity can thus enable the rational design of conditionally attenuated viral vaccines.

2022-07-26 | GSE208611 | GEO

RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

Project description:RNA features governing zinc finger antiviral protein sensitivity enable attenuated virus design

| PRJNA860213 | ENA

Modulation of host gene expression by the zinc finger antiviral protein [CLIP-seq]

Project description:Modulation of host gene expression by the zinc finger antiviral protein [CLIP-seq]

| PRJNA1147239 | ENA

Modulation of host gene expression by the zinc finger antiviral protein [RNA-seq]

Project description:Modulation of host gene expression by the zinc finger antiviral protein [RNA-seq]

| PRJNA1147233 | ENA

Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression

Project description:Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression

| PRJNA562266 | ENA

Modulation of host gene expression by the zinc finger antiviral protein [CLIP-seq]

Project description:The zinc finger antiviral protein (ZAP) depletes non-self RNAs through recognition of their elevated CpG dinucleotide content. CpG dinucleotides are sparse in most endogenous mammalian mRNAs, but a subset might potentially be modulated by ZAP. While CpG frequency alone is insufficient to predict ZAP-regulation, we developed an algorithm using experimentally determined compositional features to predict which endogenous mRNAs may be ZAP-regulated. Using ZAP-knockout mice, we demonstrate that levels of many host mRNAs that are algorithmically predicted ZAP targets are indeed increased when ZAP is absent. ZAP is interferon-inducibel and we also identify genes that are downregulated by ZAP during an innate immune response. Many ZAP-regulated gene products are extracellular matrix or of nucleosome components, whose ZAP mediated control is conserved in human cells. Overall, we provide a new tool for the prediction of ZAP target genes and reveal host mRNAs that are ZAP-regulated.

2024-09-01 | GSE274582 | GEO

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