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.
Highlights
Cells encode a variety of nucleic acid sensors that detect the presence of viral RNA or DNA by virtue of non-self features or inappropriate localization
We confirm through biochemical experiments that Zinc-finger antiviral protein (ZAP) binds PAR, both in vitro and in cells
ZAP has a modular organization and is expressed as two major isoforms called ZAP-L and ZAP-S, that arise from alternative splicing and are distinguished by the presence of a C-terminal PARP or poly(ADP-ribose) polymerase-like domain (Fig 1A)
Summary
Cells encode a variety of nucleic acid sensors that detect the presence of viral RNA or DNA by virtue of non-self features or inappropriate localization. The zinc-finger antiviral protein ZAP ( known as poly(ADP-ribose) polymerase 13 or PARP13) is one such sensor and selectively binds to viral messenger RNA or viral RNA genomes [1,2]. ZAP has a modular organization and is expressed as two major isoforms called ZAP-L and ZAP-S, that arise from alternative splicing and are distinguished by the presence of a C-terminal PARP or poly(ADP-ribose) polymerase-like domain (Fig 1A). Both isoforms contain an N-terminal RNA-binding domain (RBD) with four zinc fingers (here termed Z1 to Z4) that bind to CpG dinucleotides in RNA [5,6]. The absence of the PARP-like domain and mutagenesis of its vestigial catalytic site are reported to negatively affect ZAP antiviral activity [8,9]
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