In the present study, we reveal that Filamin A phosphorylation is induced by ORF45-mediated RSK activation during KSHV primary infection and lytic replication; consequently, ORF45-induced Filamin A phosphorylation promotes the detachment and migration of lytic KSHV-infected cells and facilitates KSHV de novo infection and cell-to-cell viral transmission through cell contact and movement during the lytic cycle. Here, RPS6KA3 is linked to infection.