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.