Abstract
One of the hallmarks of the latent phase of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is the global repression of lytic viral gene expression. Following de novo KSHV infection, the establishment of latency involves the chromatinization of the incoming viral genomes and recruitment of the host Polycomb repressive complexes (PRC1 and PRC2) to the promoters of lytic genes, which is accompanied by the inhibition of lytic genes. However, the mechanism of how PRCs are recruited to the KSHV episome is still unknown. Utilizing a genetic screen of latent genes in the context of KSHV genome, we identified the latency-associated nuclear antigen (LANA) to be responsible for the genome-wide recruitment of PRCs onto the lytic promoters following infection. We found that LANA initially bound to the KSHV genome right after infection and subsequently recruited PRCs onto the viral lytic promoters, thereby repressing lytic gene expression. Furthermore, both the DNA and chromatin binding activities of LANA were required for the binding of LANA to the KSHV promoters, which was necessary for the recruitment of PRC2 to the lytic promoters during de novo KSHV infection. Consequently, the LANA-knockout KSHV could not recruit PRCs to its viral genome upon de novo infection, resulting in aberrant lytic gene expression and dysregulation of expression of host genes involved in cell cycle and proliferation pathways. In this report, we demonstrate that KSHV LANA recruits host PRCs onto the lytic promoters to suppress lytic gene expression following de novo infection.
Highlights
It is estimated that 15%-20% of human cancers are caused by viral infections [1]
Our results indicate that the Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) hijacks host polycomb proteins to create the heterochromatin structure on the viral genome, which leads to the repression of lytic gene expression and thereby, the establishment of viral latency
To determine which of the latent genes is required for the recruitment of polycomb proteins onto the KSHV genome during de novo infection, we generated a series of latent gene KO mutant viruses using en passant mutagenesis on the KSHV BAC clone BAC16 (Fig 1A and S1 Fig)
Summary
It is estimated that 15%-20% of human cancers are caused by viral infections [1]. A hallmark of the seven known human tumor viruses is their ability to cause persistent infection of humans. During latency the lytic gene expression is repressed and only the latent genes (the latency-associated nuclear antigen (LANA or ORF73), v-Cyclin (ORF72), v-FLIP (K13 or ORF71), Kaposin (K12) and viral miRNAs) are constitutively expressed from the latency locus of the viral genome [5] These latent viral products are involved in the maintenance of viral latency, and in growth-transformation and cell cycle-deregulation, both of which can contribute to the development of KSHV-induced cancers [6]. LANA can regulate both viral and cellular gene expression by interacting with numerous transcription and epigenetic factors as well as modulating many signaling pathways [10] These LANA-associated functions have been implicated to play critical roles in the maintenance of latency by inhibiting lytic gene expression and viral pathogenesis by deregulating host signaling pathways
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