ZAP, a CCCH-Type Zinc Finger Protein, Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication and Interacts with Viral Nsp9

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens affecting many swine-producing regions. Current vaccination strategies and antiviral drugs provide only limited protection. PRRSV infection can cleave mitochondrial antiviral signaling protein (MAVS) and inhibit the induction of type I interferon. The antiviral effector molecules that are involved in host protective responses to PRRSV infection are not fully understood.Here, by using transcriptome sequencing, we found that a zinc finger antiviral protein, ZAP, is upregulated in MAVS-transfected Marc-145 cells and that ZAP suppresses PRRSV infection at the early stage of replication. We also found that the viral protein Nsp9, an RNA-dependent RNA polymerase (RdRp), interacts with ZAP. The interacting locations were mapped to the zinc finger domain of ZAP and N-terminal amino acids 150 to 160 of Nsp9. These findings suggest that ZAP is an effective antiviral factor for suppressing PRRSV infection, and they shed light on virus-host interaction.IMPORTANCE PRRSV continues to adversely impact the global swine industry. It is important to understand the various antiviral factors against PRRSV infection. Here, a zinc finger protein, termed ZAP, was screened from MAVS-induced antiviral genes by transcriptome sequencing, and it was found to remarkably suppress PRRSV replication and interact with PRRSV Nsp9. The zinc finger domain of ZAP and amino acids 150 to 160 of Nsp9 are responsible for the interaction. These findings expand the antiviral spectrum of ZAP and provide a better understanding of ZAP antiviral mechanisms, as well as virus-host interactions.

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…As such, most of its antiviral activity is independent of ADP-ribosylation. Since its discovery, ZAP has been shown to inhibit the replication of several viral families, including retroviruses, alphaviruses, filoviruses, picornaviruses, herpesviruses, arteriviruses, orthomyxoviruses, flaviviruses, and hepatitis B virus (Bick et al 2003;Muller et al 2007;Zhu et al 2011;Wang et al 2012;Xuan et al 2012;Mao et al 2013;Xuan et al 2013;Li et al 2015Li et al , 2015aChiu et al 2018;Xie et al 2018;Zhao et al 2019). ZAP is transcribed into four different isoforms, with ZAPL and ZAPS being the most studied .…”

The Roles of CCCH Zinc-Finger Proteins in Plant Abiotic Stress Tolerance

“…CCCH zinc-finger proteins can also exert their functions by interacting with other proteins [ 135 ]. The mammalian CCCH zinc-finger protein TTP interacts with many different types of proteins through its N terminus, C terminus, or zinc-finger structure [ 136 ].…”

ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication

“…One classic example of an innate immunity component is the zinc-finger antiviral protein (ZAP), which is constitutively expressed in many cells and induced upon pathogen sensing and in response to interferon [4–6]. Initially identified as an anti-Moloney murine leukemia virus (MLV) factor [7], ZAP exhibits broad antiviral activity, for example inhibiting other retroviruses [8], LINE-1 retrotransposition [9], alphaviruses [10], filoviruses [11], enteroviruses [12], hepatitis B virus [13], influenza [14] and porcine reproductive and respiratory virus [15]. While it is not clear how ZAP is able to exert such broad antiviral function, a recent study postulated that increased CpG content may underlie susceptibility of a virus to ZAP’s antiviral effects [16].…”