K13 blocks KSHV lytic replication and deregulates vIL6 and hIL6 expression: a model of lytic replication induced clonal selection in viral oncogenesis.
BACKGROUND
Accumulating evidence suggests that dysregulated expression of lytic genes plays an important role in KSHV (Kaposi's sarcoma associated herpesvirus) tumorigenesis. However, the molecular events leading to the dysregulation of KSHV lytic gene expression program are incompletely understood.


RESULTS
We have studied the effect of KSHV-encoded latent protein vFLIP K13, a potent activator of the NF-kappaB pathway, on lytic reactivation of the virus. We demonstrate that K13 antagonizes RTA, the KSHV lytic-regulator, and effectively blocks the expression of lytic proteins, production of infectious virions and death of the infected cells. Induction of lytic replication selects for clones with increased K13 expression and NF-kappaB activity, while siRNA-mediated silencing of K13 induces the expression of lytic genes. However, the suppressive effect of K13 on RTA-induced lytic genes is not uniform and it fails to block RTA-induced viral IL6 secretion and cooperates with RTA to enhance cellular IL-6 production, thereby dysregulating the lytic gene expression program.


CONCLUSIONS
Our results support a model in which ongoing KSHV lytic replication selects for clones with progressively higher levels of K13 expression and NF-kappaB activity, which in turn drive KSHV tumorigenesis by not only directly stimulating cellular survival and proliferation, but also indirectly by dysregulating the viral lytic gene program and allowing non-lytic production of growth-promoting viral and cellular genes. Lytic Replication-Induced Clonal Selection (LyRICS) may represent a general mechanism in viral oncogenesis.
Zhao
Jinshun
J
Division of Hematology-Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Punj
Vasu
V
Matta
Hittu
H
Mazzacurati
Lucia
L
Schamus
Sandra
S
Yang
Yanqiang
Y
Yang
Tianbing
T
Hong
Yan
Y
Chaudhary
Preethello M
PM
D002460:Cell Line; D004261:DNA Replication; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D005814:Genes, Viral; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry; D015850:Interleukin-6 / Q000378:metabolism*; D009369:Neoplasms / Q000821:virology*; D034741:RNA, Small Interfering / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry; D014779:Virus Replication
D017874:Immediate-Early Proteins; D015850:Interleukin-6; D034741:RNA, Small Interfering; D014764:Viral Proteins