Rottlerin inhibits macropinocytosis of Porcine Reproductive and Respiratory Syndrome Virus through the PKCδ-Cofilin signaling pathway

Rottlerin exerts antiviral activity against various enveloped viruses, yet the mechanism by which it inhibits viral replication and the associated signaling pathways remains unclear. Here, we investigated the mechanisms for the antiviral effects of rottlerin against Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) in vitro. We demonstrate that PRRSV enters host cells via macropinocytosis. Rottlerin, a PKCδ inhibitor, partially inhibits PRRSV entry by decreasing actin polymerization, as evidenced by alterations in actin dynamics. LIM domain kinase 1 (LIMK1) is essential for PRRSV replication, and PRRSV infection-induced cofilin activation, which was reversed by rottlerin treatment. Our findings suggest that a subset of PRRSV utilizes PKCδ-mediated actin dynamics to enter cells via macropinocytosis, and that rottlerin is a potential antiviral molecule targeting this entry pathway.