Abstract
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic pathogen that displays latent and lytic life cycles. In KS lesions, infiltrated immune cells, secreted viral and/or cellular cytokines, and hypoxia orchestrate a chronic pro-lytic microenvironment that can promote KSHV reactivation. However, only a small subset of viruses spontaneously undergoes lytic replication in this pro-lytic microenvironment while the majority remains in latency. Here, we show that the expression of the Notch ligand JAG1 is induced by KSHV-encoded replication and transcription activator (RTA) during reactivation. JAG1 up-regulation activates Notch signaling in neighboring cells and prevents viral lytic replication. The suppression of JAG1 and Notch1 with inhibitors or small interfering RNA promotes lytic replication in the presence of RTA induction or under conditions of hypoxia. The underlying mechanism involves the Notch downstream effector hairy and enhancer of split 1 (Hes1), which directly binds lytic gene promoters and attenuates viral lytic gene expression. RTA interacts with lymphoid enhancer-binding factor 1 (LEF1), disrupts LEF1/Groucho/TLE suppressive complexes and releases LEF1 to activate JAG1 expression. Taken together, our results suggest that cells with viral lytic replication can inhibit KSHV reactivation in neighboring cells through an RTA-JAG1-Notch pathway. These data provide insight into the mechanism by which the virus maintains the balance between lytic and latent infection in the pro-lytic tumor microenvironment.
Highlights
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a large double-stranded DNA virus with a biphasic life cycle [1]
Assessment of the expression of the core components of the Notch signaling pathway showed a significant up-regulation of Notch1 and JAG1 at mRNA and protein levels in iSLK.RGB cells (Figs 1A and S1A)
As Notch activation is initiated by ligand-receptor interaction through cell-to-cell contact, we examined whether replication and transcription activator (RTA) induced JAG1 could activate Notch signaling in neighboring cells in trans
Summary
Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a large double-stranded DNA virus with a biphasic life cycle [1]. KS tissues perfuse with slit-like vessels and a large number of infiltrated inflammatory cells exhibit a pro-lytic milieu that potentially promotes KSHV to be reactivated from latency [19]. The latently infected cells are likely to become stressed, and the virus can be stimulated to undergo lytic replication associated with tumor progression. Reactivation is a rare event in KS tissues, with approximately 1–3% of spindle cells displaying lytic replicative markers [19]. In this regard, the controlled lytic replication observed in KS tissues suggests its pathological importance for disease development. The mechanism by which KSHV regulates this process remains unclear
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