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The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding.

ABSTRACT: Recognition of viral dsRNA by Toll-like receptor 3 (TLR3) leads to the induction of downstream antiviral effectors and the innate antiviral immune response. Here, we identified the zinc-finger FYVE domain-containing protein ZFYVE1, a guanylate-binding protein (GBP), as a positive regulator of TLR3-mediated signaling. Overexpression of ZFYVE1 promoted the transcription of downstream antiviral genes upon stimulation with the synthetic TLR3 ligand poly(I:C). Conversely, ZFYVE1 deficiency had the opposite effect. Zfyve1^-/- mice were less susceptible than wild-type mice to inflammatory death induced by poly(I:C) but not LPS. ZFYVE1 was associated with TLR3, and the FYVE domain of ZFYVE1 and the ectodomain of TLR3 were shown to be responsible for their interaction. ZFYVE1 was bound to poly(I:C) and increased the binding affinity of TLR3 to poly(I:C). These findings suggest that ZFYVE1 plays an important role in the TLR3-mediated innate immune and inflammatory responses by promoting the ligand binding of TLR3.

SUBMITTER: Zhong X

PROVIDER: S-EPMC7331751 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3.

Project description:Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-? (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3-/- mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.

| S-EPMC7232131 | biostudies-literature

Zinc Finger RNA-Binding Protein Zn72D Regulates ADAR-Mediated RNA Editing in Neurons.

Project description:Adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, alters RNA sequences from those encoded by DNA. These editing events are dynamically regulated, but few trans regulators of ADARs are known in vivo. Here, we screen RNA-binding proteins for roles in editing regulation with knockdown experiments in the Drosophila brain. We identify zinc-finger protein at 72D (Zn72D) as a regulator of editing levels at a majority of editing sites in the brain. Zn72D both regulates ADAR protein levels and interacts with ADAR in an RNA-dependent fashion, and similar to ADAR, Zn72D is necessary to maintain proper neuromuscular junction architecture and fly mobility. Furthermore, Zn72D's regulatory role in RNA editing is conserved because the mammalian homolog of Zn72D, Zfr, regulates editing in mouse primary neurons. The broad and conserved regulation of ADAR editing by Zn72D in neurons sustains critically important editing events.

| S-EPMC7306179 | biostudies-literature

Zinc finger RNA binding protein Zn72D regulates ADAR-mediated RNA editing in neurons

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-05-08 | GSE126631 | GEO

ZFC3H1, a zinc finger protein, modulates IL-8 transcription by binding with celastramycin A, a potential immune suppressor.

Project description:Celastramycin A, a small molecule that inhibits the production of antibacterial peptides in an ex vivo culture system of Drosophila, suppresses the TNFα-mediated induction of IL-8 in mammalian cells. To understand its molecular mechanism, we examined Celastramycin A binding proteins and investigated their biological functions. Our screening and subsequent pull-down assay revealed ZFC3H1 (also known as CCDC131 or CSRC2), an uncharacterized zinc finger protein, as a Celastramycin A binding protein. The knockdown of ZFC3H1 reduced IL-8 expression levels in the TNFα-stimulated lung carcinoma cell line, LU99, and UV-irradiated HeLa cells. Based on reporter assay results, we concluded that ZFC3H1 participates in the transcriptional activation of IL-8. The findings of our UV-irradiation experiments implied that ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. Thus, we designated ZFC3H1 as a mammalian target of Celastramycin A (mTOC).

| S-EPMC4182580 | biostudies-literature

Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity.

Project description:Interferons (IFNs) direct innate and acquired immune responses and, accordingly, are used therapeutically to treat a number of diseases, yet the diverse effects they elicit are not fully understood. Here, we identified the promyelocytic leukemia zinc finger (PLZF) protein as a previously unrecognized component of the IFN response. IFN stimulated an association of PLZF with promyelocytic leukemia protein (PML) and histone deacetylase 1 (HDAC1) to induce a decisive subset of IFN-stimulated genes (ISGs). Consequently, PLZF-deficient mice had a specific ISG expression defect and as a result were more susceptible to viral infection. This susceptibility correlated with a marked decrease in the expression of the key antiviral mediators and an impaired IFN-mediated induction of natural killer cell function. These results provide new insights into the regulatory mechanisms of IFN signaling and the induction of innate antiviral immunity.

| S-EPMC2711215 | biostudies-literature

In-depth study of DNA binding of Cys2His2 finger domains in testis zinc-finger protein.

Project description:Previously, we identified that both fingers 1 and 2 in the three Cys2His2 zinc-finger domains (TZD) of testis zinc-finger protein specifically bind to its cognate DNA; however, finger 3 is non-sequence-specific. To gain insights into the interaction mechanism, here we further investigated the DNA-binding characteristics of TZD bound to non-specific DNAs and its finger segments bound to cognate DNA. TZD in non-specific DNA binding showed smaller chemical shift perturbations, as expected. However, the direction of shift perturbation, change of DNA imino-proton NMR signal, and dynamics on the 15N backbone atom significantly differed between specific and non-specific binding. Using these unique characteristics, we confirmed that the three single-finger segments (TZD1, TZD2 and TZD3) and the two-finger segment (TZD23) non-specifically bind to the cognate DNA. In comparison, the other two-finger segment (TZD12) binding to the cognate DNA features simultaneous non-specific and semi-specific binding, both slowly exchanged in terms of NMR timescale. The process of TZD binding to the cognate DNA is likely stepwise: initially TZD non-specifically binds to DNA, then fingers 1 and 2 insert cooperatively into the major groove of DNA by semi-specific binding, and finally finger 3 non-specifically binds to DNA, which promotes the specific binding on fingers 1 and 2 and stabilizes the formation of a specific TZD-DNA complex.

| S-EPMC5383199 | biostudies-literature

DNA binding specificities of the long zinc-finger recombination protein PRDM9.

Project description:BackgroundMeiotic recombination ensures proper segregation of homologous chromosomes and creates genetic variation. In many organisms, recombination occurs at limited sites, termed 'hotspots', whose positions in mammals are determined by PR domain member 9 (PRDM9), a long-array zinc-finger and chromatin-modifier protein. Determining the rules governing the DNA binding of PRDM9 is a major issue in understanding how it functions.ResultsMouse PRDM9 protein variants bind to hotspot DNA sequences in a manner that is specific for both PRDM9 and DNA haplotypes, and that in vitro binding parallels its in vivo biological activity. Examining four hotspots, three activated by Prdm9Cst and one activated by Prdm9Dom2, we found that all binding sites required the full array of 11 or 12 contiguous fingers, depending on the allele, and that there was little sequence similarity between the binding sites of the three Prdm9Cst activated hotspots. The binding specificity of each position in the Hlx1 binding site, activated by Prdm9Cst, was tested by mutating each nucleotide to its three alternatives. The 31 positions along the binding site varied considerably in the ability of alternative bases to support binding, which also implicates a role for additional binding to the DNA phosphate backbone.ConclusionsThese results, which provide the first detailed mapping of PRDM9 binding to DNA and, to our knowledge, the most detailed analysis yet of DNA binding by a long zinc-finger array, make clear that the binding specificities of PRDM9, and possibly other long-array zinc-finger proteins, are unusually complex.

| S-EPMC4053984 | biostudies-literature

An expanded binding model for Cys2His2 zinc finger protein-DNA interfaces.

Project description:Cys(2)His(2) zinc finger (C2H2-ZF) proteins comprise the largest class of eukaryotic transcription factors. The 'canonical model' for C2H2-ZF protein-DNA interaction consists of only four amino acid-nucleotide contacts per zinc finger domain, and this model has been the basis for several efforts for computationally predicting and experimentally designing protein-DNA interfaces. Here, we perform a systematic analysis of structural and experimental binding data and find that, in addition to the canonical contacts, several other amino acid and base pair combinations frequently play a role in C2H2-ZF protein-DNA binding. We suggest an expansion of the canonical C2H2-ZF model to include one to three additional contacts, and show that computational approaches including these additional contacts improve predictions of DNA targets of zinc finger proteins.

| S-EPMC3402046 | biostudies-literature

Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression.

Project description:In primates, puberty is unleashed by increased GnRH release from the hypothalamus following an interval of juvenile quiescence. GWAS implicates Zinc finger (ZNF) genes in timing human puberty. Here we show that hypothalamic expression of several ZNFs decreased in agonadal male monkeys in association with the pubertal reactivation of gonadotropin secretion. Expression of two of these ZNFs, GATAD1 and ZNF573, also decreases in peripubertal female monkeys. However, only GATAD1 abundance increases when gonadotropin secretion is suppressed during late infancy. Targeted delivery of GATAD1 or ZNF573 to the rat hypothalamus delays puberty by impairing the transition of a transcriptional network from an immature repressive epigenetic configuration to one of activation. GATAD1 represses transcription of two key puberty-related genes, KISS1 and TAC3, directly, and reduces the activating histone mark H3K4me2 at each promoter via recruitment of histone demethylase KDM1A. We conclude that GATAD1 epitomizes a subset of ZNFs involved in epigenetic repression of primate puberty.

| S-EPMC4703871 | biostudies-literature

The apple DNA-binding one zinc-finger protein MdDof54 promotes drought resistance.

Project description:DNA-binding one zinc-finger (Dof) proteins constitute a family of transcription factors with a highly conserved Dof domain that contains a C2C2 zinc-finger motif. Although several studies have demonstrated that Dof proteins are involved in multiple plant processes, including development and stress resistance, the functions of these proteins in drought stress resistance are largely unknown. Here, we report the identification of the MdDof54 gene from apple and document its positive roles in apple drought resistance. After long-term drought stress, compared with nontransgenic plants, MdDof54 RNAi plants had significantly shorter heights and weaker root systems; the transgenic plants also had lower shoot and root hydraulic conductivity, as well as lower photosynthesis rates. By contrast, compared with nontransgenic plants, MdDof54-overexpressing plants had higher photosynthesis rates and shoot hydraulic conductivity under long-term drought stress. Moreover, compared with nontransgenic plants, MdDof54-overexpressing plants had higher survival percentages under short-term drought stress, whereas MdDof54 RNAi plants had lower survival percentages. MdDof54 RNAi plants showed significant downregulation of 99 genes and significant upregulation of 992 genes in response to drought, and 366 of these genes were responsive to drought. We used DAP-seq and ChIP-seq analyses to demonstrate that MdDof54 recognizes cis-elements that contain an AAAG motif. Taken together, our results provide new information on the functions of MdDof54 in plant drought stress resistance as well as resources for apple breeding aimed at the improvement of drought resistance.

| S-EPMC7704620 | biostudies-literature

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