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  1. Article ; Online: Origin and evolution of the zinc finger antiviral protein.

    Gonçalves-Carneiro, Daniel / Takata, Matthew A / Ong, Heley / Shilton, Amanda / Bieniasz, Paul D

    PLoS pathogens

    2021  Volume 17, Issue 4, Page(s) e1009545

    Abstract: The human zinc finger antiviral protein (ZAP) recognizes RNA by binding to CpG dinucleotides. Mammalian transcriptomes are CpG-poor, and ZAP may have evolved to exploit this feature to specifically target non-self viral RNA. Phylogenetic analyses reveal ... ...

    Abstract The human zinc finger antiviral protein (ZAP) recognizes RNA by binding to CpG dinucleotides. Mammalian transcriptomes are CpG-poor, and ZAP may have evolved to exploit this feature to specifically target non-self viral RNA. Phylogenetic analyses reveal that ZAP and its paralogue PARP12 share an ancestral gene that arose prior to extensive eukaryote divergence, and the ZAP lineage diverged from the PARP12 lineage in tetrapods. Notably, the CpG content of modern eukaryote genomes varies widely, and ZAP-like genes arose subsequent to the emergence of CpG-suppression in vertebrates. Human PARP12 exhibited no antiviral activity against wild type and CpG-enriched HIV-1, but ZAP proteins from several tetrapods had antiviral activity when expressed in human cells. In some cases, ZAP antiviral activity required a TRIM25 protein from the same or related species, suggesting functional co-evolution of these genes. Indeed, a hypervariable sequence in the N-terminal domain of ZAP contributed to species-specific TRIM25 dependence in antiviral activity assays. Crosslinking immunoprecipitation coupled with RNA sequencing revealed that ZAP proteins from human, mouse, bat and alligator exhibit a high degree of CpG-specificity, while some avian ZAP proteins appear more promiscuous. Together, these data suggest that the CpG- rich RNA directed antiviral activity of ZAP-related proteins arose in tetrapods, subsequent to the onset of CpG suppression in certain eukaryote lineages, with subsequent species-specific adaptation of cofactor requirements and RNA target specificity.
    MeSH term(s) Alligators and Crocodiles ; Animals ; Antiviral Agents/metabolism ; Cells, Cultured ; Chickens ; Ducks ; Eagles ; Evolution, Molecular ; Finches ; HEK293 Cells ; Humans ; Mice ; Phylogeny ; RNA-Binding Proteins/genetics ; Transcription Factors/genetics ; Tripartite Motif Proteins/genetics ; Turkey ; Ubiquitin-Protein Ligases/genetics ; Zebrafish ; Zinc Fingers/genetics
    Chemical Substances Antiviral Agents ; RNA-Binding Proteins ; Transcription Factors ; Tripartite Motif Proteins ; ZC3HAV1 protein, human ; TRIM25 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2021-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1009545
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Poly(ADP-ribose) potentiates ZAP antiviral activity.

    Xue, Guangai / Braczyk, Klaudia / Gonçalves-Carneiro, Daniel / Dawidziak, Daria M / Sanchez, Katarzyna / Ong, Heley / Wan, Yueping / Zadrozny, Kaneil K / Ganser-Pornillos, Barbie K / Bieniasz, Paul D / Pornillos, Owen

    PLoS pathogens

    2022  Volume 18, Issue 2, Page(s) e1009202

    Abstract: Zinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an antiviral factor that selectively targets viral RNA for degradation. ZAP is active against both DNA and RNA viruses, including important human pathogens ... ...

    Abstract Zinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an antiviral factor that selectively targets viral RNA for degradation. ZAP is active against both DNA and RNA viruses, including important human pathogens such as hepatitis B virus and type 1 human immunodeficiency virus (HIV-1). ZAP selectively binds CpG dinucleotides through its N-terminal RNA-binding domain, which consists of four zinc fingers. ZAP also contains a central region that consists of a fifth zinc finger and two WWE domains. Through structural and biochemical studies, we found that the fifth zinc finger and tandem WWEs of ZAP combine into a single integrated domain that binds to poly(ADP-ribose) (PAR), a cellular polynucleotide. PAR binding is mediated by the second WWE module of ZAP and likely involves specific recognition of an adenosine diphosphate-containing unit of PAR. Mutation of the PAR binding site in ZAP abrogates the interaction in vitro and diminishes ZAP activity against a CpG-rich HIV-1 reporter virus and murine leukemia virus. In cells, PAR facilitates formation of non-membranous sub-cellular compartments such as DNA repair foci, spindle poles and cytosolic RNA stress granules. Our results suggest that ZAP-mediated viral mRNA degradation is facilitated by PAR, and provides a biophysical rationale for the reported association of ZAP with RNA stress granules.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Crystallography, X-Ray ; HEK293 Cells ; HIV-1/metabolism ; HeLa Cells ; Humans ; Leukemia Virus, Murine/metabolism ; Mice ; Mutation ; Poly Adenosine Diphosphate Ribose/metabolism ; Protein Binding ; Protein Conformation ; Protein Domains ; RNA Stability ; RNA, Viral ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/metabolism ; RNA-Binding Proteins/pharmacology ; Zinc Fingers
    Chemical Substances Antiviral Agents ; RNA, Viral ; RNA-Binding Proteins ; ZC3HAV1 protein, human ; Poly Adenosine Diphosphate Ribose (26656-46-2)
    Language English
    Publishing date 2022-02-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1009202
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Structure of the zinc-finger antiviral protein in complex with RNA reveals a mechanism for selective targeting of CG-rich viral sequences.

    Meagher, Jennifer L / Takata, Matthew / Gonçalves-Carneiro, Daniel / Keane, Sarah C / Rebendenne, Antoine / Ong, Heley / Orr, Victoria K / MacDonald, Margaret R / Stuckey, Jeanne A / Bieniasz, Paul D / Smith, Janet L

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 48, Page(s) 24303–24309

    Abstract: Infection of animal cells by numerous viruses is detected and countered by a variety of means, including recognition of nonself nucleic acids. The zinc finger antiviral protein (ZAP) depletes cytoplasmic RNA that is recognized as foreign in mammalian ... ...

    Abstract Infection of animal cells by numerous viruses is detected and countered by a variety of means, including recognition of nonself 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 with endogenous mRNAs. Here, we determined a crystal structure of a protein-RNA complex containing the N-terminal, 4-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 4 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, cross-linking 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 RNA-binding specificity among 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.
    MeSH term(s) Binding Sites ; Crystallography, X-Ray ; Fluorescence Polarization ; GC Rich Sequence ; HEK293 Cells ; HIV-1/genetics ; Humans ; Models, Molecular ; Mutagenesis ; Mutation ; Protein Domains ; RNA, Viral/chemistry ; RNA, Viral/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Repressor Proteins/chemistry ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Zinc Fingers
    Chemical Substances RNA, Viral ; RNA-Binding Proteins ; Repressor Proteins ; YLPM1 protein, human
    Language English
    Publishing date 2019-11-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1913232116
    Database MEDical Literature Analysis and Retrieval System OnLINE

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