A comprehensive PDCoV-host proteome interaction map reveals potential antiviral targets

TL;DR

This study maps interactions between PDCoV and host proteins, identifying SYNCRIP as a key antiviral target for coronaviruses.

Contribution

The study introduces a comprehensive PDCoV-host proteome interaction map and identifies SYNCRIP as a novel host restriction factor.

Findings

SYNCRIP interacts with PDCoV N protein and blocks its ubiquitin-proteasome degradation.

Isoforsythiaside, a SYNCRIP inhibitor, shows strong antiviral effects in vitro and in vivo.

The PDCoV-host interaction network highlights host processes critical for viral replication.

Abstract

Porcine deltacoronavirus (PDCoV), an enteric member of the coronavirus family, has emerged globally over the past decade, causing significant impacts on the swine industry. While studies of virus-host protein interactions provide crucial insights into viral engagement with host cells during infection, research specifically targeting PDCoV-host interaction factors remains limited. To identify host proteins involved in PDCoV replication, comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was employed to identify host proteins interacting with the PDCoV genomic RNA. Concurrently, affinity purification mass spectrometry (AP-MS) was utilized to identify host interactors of PDCoV-encoded proteins. A total of 671 host proteins were identified in our analysis. These host interactors participate in diverse cellular processes, including extensive representation of metabolic enzymes, transcription factors, RNA-binding proteins (RBPs), and intracellular signal transduction components. Construction of a comprehensive PDCoV-host protein interaction network map revealed that SYNCRIP (heterogeneous nuclear ribonucleoprotein Q, hnRNP Q), functions as a novel host restriction factor with PDCoV. SYNCRIP interacts with the N proteins of multiple coronaviruses and competitively displaces HUWE1 to bind the PDCoV N protein, thereby blocking its ubiquitin-proteasome-mediated degradation. Furthermore, Isoforsythiaside, a small-molecule inhibitor designed to target SYNCRIP, demonstrated substantial antiviral potential both in vitro and in vivo. In summary, this study provides a comprehensive catalog of functional PDCoV viral RNA (vRNA)/viral Protein (vProtein)-host protein interactions. This resource not only informs the understanding of pan-coronavirus infection mechanisms but also nominates host cellular processes as potential targets for antiviral intervention.

Porcine deltacoronavirus (PDCoV) demonstrates significant cross-species infection potential, with its spillover risk to human hosts posing a major public health threat. Elucidating the molecular interaction mechanisms between the virus and host is of critical scientific value for antiviral drug target discovery. In this study, we systematically constructed a virus-host interaction network centered on PDCoV’s infectious RNA and structural proteins, identifying host interaction proteins involved in key biological processes, including metabolic regulation, translation and transcription, vesicular transport, and ubiquitination modification. Network analysis revealed the molecular mechanism by which PDCoV hijacks host cells for life program reprogramming. Further functional investigation of the key hub protein SYNCRIP demonstrated that it significantly promotes viral replication by competitively binding to the viral N protein, thereby blocking the ubiquitination and degradation pathway mediated by HUWE1. In vivo and in vitro experiments confirmed that targeting SYNCRIP exerts potent antiviral effects, providing a novel strategy for antiviral drug development based on virus-host interaction networks. This study validates that systematic analysis of virus-host interaction networks offers significant advantages in identifying novel antiviral targets.

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