Porcine epidemic diarrhea virus infection activates SREBP2 and induces RORγ expression to enhance cholesterol biosynthesis and virus replication

Cholesterol is a main lipid component of host cell membranes and plays an essential role in virus Infection and replication. Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus that replicates efficiently in intestinal epithelial cells, requires abundant Cholesterol to complete its replication cycle. However, the mechanisms by which PEDV modulates host Cholesterol biosynthesis remain incompletely understood. Here, we report that PEDV Infection activates the sterol regulatory element-binding protein 2 (SREBP2) and induces the expression of the retinoic acid receptor-related Orphan Receptor γ (RORγ). These two transcription factors cooperate to induce the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in Cholesterol biosynthesis. Silencing RORγ or pharmacologic inhibition using XY018 or GSK805 suppresses HMGCR expression, reduces Cholesterol synthesis, and impedes PEDV replication. Conversely, RORγ overexpression enhances Cholesterol biosynthesis-related gene expression and viral replication. Co-inhibition of SREBP2 and RORγ by their specific inhibitors synergistically suppresses PEDV replication. Exogenous Cholesterol supplementation antagonizes the inhibitory effects of RORγ inhibitors on virus replication. Mechanistically, PEDV-induced RORγ expression relies on TAK1 and its downstream kinases JNK and IKK, which activate AP-1 and NF-κB signaling, respectively. Our study provides evidence that PEDV Infection activates the TAK1-JNK/IKK-RORγ axis to drive Cholesterol biosynthesis and support viral replication.

Cholesterol; PEDV; RORγ; RORγ inhibitors; SREBP2; TAK1.