Poly(ADP-ribose) potentiates ZAP antiviral activity

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• Zinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an intrinsic host defense factor against viral infections.
• ZAP exhibits broad-spectrum antiviral activity against both DNA and RNA viruses, including significant human pathogens like Hepatitis B virus and HIV-1.
• The antiviral mechanism of ZAP involves the selective targeting and degradation of viral RNA.

Purpose of the Study:

• To elucidate the structural and biochemical basis of ZAP's interaction with poly(ADP-ribose) (PAR).
• To investigate the role of PAR binding in ZAP's antiviral activity.

Main Methods:

• Structural and biochemical studies were employed to characterize the ZAP-PAR interaction.
• Mutagenesis of the putative PAR binding site within ZAP was performed.
• In vitro assays and reporter virus systems were used to assess ZAP activity.

Main Results:

• The fifth zinc finger and tandem WWE domains of ZAP form an integrated domain that binds PAR.
• PAR binding is primarily mediated by the second WWE module, involving recognition of ADP-containing units within PAR.
• Mutation of the PAR binding site significantly reduced ZAP's interaction with PAR in vitro and diminished its antiviral efficacy against CpG-rich HIV-1 and murine leukemia virus.

Conclusions:

• PAR binding is a critical component of ZAP's antiviral function, facilitating viral mRNA degradation.
• The findings provide a biophysical explanation for the observed association of ZAP with cellular RNA stress granules, which are known to be influenced by PAR.