Key result
Long ZAP isoform preferentially binds viral RNA and recruits key enzymes to drive complete decay.
Why the study?
Why ZAP isoforms differ in antiviral activity and how they recruit cofactors to mediate RNA decay remained unclear.
This study elucidates the molecular mechanism by which the long isoform of ZAP coordinates multiple enzymes to mediate the complete decay of viral RNA.
Answers are grounded in this paper and cite their sources.
Elucidates ZMD cofactor recruitment and isoform differences; leaves open therapeutic targeting of host RNA decay in viral infection.
Zinc-finger antiviral protein (ZAP)-mediated RNA decay (ZMD) restricts the replication of viruses containing CpG dinucleotide clusters. However, why ZAP isoforms differ in antiviral activity and how they recruit cofactors to mediate RNA decay is unclear. Therefore, we determined the ordered events of the ZMD pathway. The long ZAP isoform preferentially binds viral RNA and has distinct binding motifs compared to the short isoform. The endoribonuclease KHNYN then cleaves viral RNA at positions of ZAP binding. The 5' cleavage fragment undergoes TUT4/TUT7-mediated 3' uridylation and degradation by DIS3L2. The 3' cleavage fragment is degraded by XRN1. ZAP and TRIM25 interact with KHNYN, TUT7, DIS3L2, and XRN1 in an RNase-resistant manner. Viral infection promotes the interaction between TRIM25 with these enzymes, leading to viral RNA decay while also decreasing the abundance of cellular transcripts. Overall, the long isoform of ZAP recruits key enzymes to assemble an RNA decay complex on viral RNA.
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Bouton et al. (2026) studied Viral infection. ZAP long isoform vs. ZAP short isoform was evaluated on Mechanism of ZAP-mediated RNA decay. The long isoform of ZAP preferentially binds viral RNA and recruits key enzymes, including KHNYN, TUT4/7, DIS3L2, and XRN1, to assemble an RNA decay complex that mediates complete viral RNA decay.
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