The long isoform of ZAP widely restricts Paramyxoviruses

Paramyxoviruses (PVs) are negative-sense RNA viruses that are important in human and animal health, and can cause severe zoonotic diseases. We screened a wide range of animal and human PV matrix proteins for host interactions, and found that the long (L) isoform of the host protein ZAP (zinc-finger antiviral protein) interacted with all the tested viral matrixes. ZAP-L is constitutively expressed, has a prenlyation motif for membrane-localization, and primarily mediates antiviral activity by binding and degrading viral RNAs through the exosome complex. However, ZAP restriction of PVs has not been demonstrated in the literature. We found that knockdown of ZAP-L results in increased replication of a panel of five human and animal PVs. Overexpression of ZAP-L (but not ZAP-short) restricts replication of PVs in a reciprocal pattern – with the notable exception of Sendai virus (SeV) – and as with other viruses, mutating the prenylation motif of ZAP-L abolishes restriction. RT-qPCR of PV RNAs and pulled-down RNAs does not indicate specific targeting of a viral transcript by ZAP-L, although overall genome abundance is reduced. Finally, immunoprecipitation of ZAP shows an additional RNA-independent interaction between ZAP-L and SeV-nucleocapsid not found with HPIV3-nucleocapsid, a closely-related PV. Thus, we have observed that ZAP-L interacts with the matrix of, and restricts replication of, a wide range of paramyxoviruses. A PV that is not restricted (SeV), has an additional interaction with ZAP via its nucleocapsid protein that may ameliorate ZAP restriction. Investigating ZAP-related restriction differences between closely-related PVs may shed light on anti-viral mechanisms of ZAP.