105
The RTA protein (691 amino acids and 110 kDa) has an N-terminal DNA-bindingdomain and a C-terminal activation domain that can be phosphorylated during lytic
reactivation, and it is regarded as both an initiator and a controller of KSHV lytic
DNA replication [ 141 ]. RTA acts as the latent-lytic switch that induces KSHV lytic
reactivation by transcriptionally activating its own promoter. Moreover, RTA tran-
scriptionally activates at least 19 genes through direct binding to their promoters,
including ORF8, K4.1, K5, PAN, ORF16, ORF29, ORF45, ORF50, K8, K10.1,
ORF59, K12, LANA, K14/vGPCR, K15, the two origins of lytic replication
OriLyt-L and OriLyt-R, and the miRNA cluster, inducing latent cells to disrupt
latency and complete the lytic cascade. Among these 19 genes, the highest activa-
tion by ORF50 is observed in the PAN promoter, which drives the transcription of
an abundant noncoding PAN RNA [ 142 ]. Direct DNA binding by RTA is not the
only approach by which RTA transactivates promoters. RTA can also target other
promoters by interacting with RBP-Jk (known as a transcriptional repressor), which
can be converted to an activator via the activation domain of RTA [ 143 ]. Recent
research reported a new mechanism by which KSHV RTA activates the Notch sig-
naling pathway in neighboring cells to inhibit lytic gene expression, which main-
tains these cells in the latent phase [ 144 ].
In conclusion, KSHV lytic reactivation is a complex process that involves a com-bination of both viral and cellular factors. RTA plays a pivotal role during this pro-
cess. Lytic reactivation is not only important for infectious virus production but also
fundamental for tumor growth, as shown in animal models [ 145 ].
7.4.3 Switch Between Latent and Lytic Proteins
LANA and RTA, the two major proteins of KSHV, interact with each other and
control the switch between latency and lytic reactivation by targeting the RBP-Jκ
effector protein, which is a major transcriptional repressor of the Notch signaling
pathway. RTA can transactivate several viral genes, inducing lytic reactivation of
latent cells. Therefore, regulation of the expression and function of RTA is vital for
the latent-lytic balance and the fate of infected cells. LANA interacts with the
RBP-Jκ effector protein to repress the promoter of RTA. LANA competes with
RTA for binding to RBP-Jκ, inhibiting RTA self-activation and maintaining the
cells in latency. In addition, the RTA protein can activate the expression of LANA
by interacting with the RBP-Jκ effector protein on the promoter of LANA during
de novo infection, contributing to the establishment of KSHV latency [ 108 , 146 ].
Therefore, the interaction between LANA and RTA proteins in KSHV-infected
cells controls the molecular transition between latency and lytic reactivation
(Fig. 7.2).
7 KSHV Epidemiology and Molecular Biology