Fig 8. A proposed working model.

RTA up-regulates JAG1 expression by disrupting LEF1/TLE suppressive complex via competitively binding with LEF1. Elevated membrane-bound JAG1 in RTA expressing cells interacts with Notch receptors and subsequently activates Notch signaling by producing higher level of Notch Intracellular Domain (ICN) in neighboring cells. Notch downstream effector Hes1 is up-regulated in response to activated Notch signaling. Hes1 directly binds and suppresses RTA and lytic gene promoters which in turn inhibits KSHV reactivation in the context of a specific microenvironment that drives lytic replication.