Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) latently infects host cells and establishes lifelong persistence as an extra-chromosomal episome in the nucleus. To persist in proliferating cells, the viral genome typically replicates once per cell cycle and is distributed into daughter cells. This process involves host machinery utilized by KSHV, however the underlying mechanisms are not fully elucidated. In present study, we found that N-Myc downstream regulated gene 1 (NDRG1), a cellular gene known to be non-detectable in primary B cells and endothelial cells which are the major cell types for KSHV infection in vivo, was highly upregulated by KSHV in these cells. We further demonstrated that the high expression of NDRG1 was regulated by latency-associated nuclear antigen (LANA), the major viral latent protein which tethers the viral genome to host chromosome and plays an essential role in viral genome maintenance. Surprisingly, knockdown of NDRG1 in KSHV latently infected cells resulted in a significant decrease of viral genome copy number in these cells. Interestingly, NDRG1 can directly interact with proliferating cell nuclear antigen (PCNA), a cellular protein which functions as a DNA polymerase clamp during DNA replication. Intriguingly, we found that NDRG1 forms a complex with LANA and PCNA and serves as a scaffold protein bridging these two proteins. We further demonstrated that NDRG1 is critical for mediating LANA to recruit PCNA onto terminal repeat (TR) of KSHV genome, and facilitates viral DNA replication and episome persistence. Taken together, our findings suggest that NDRG1 plays an important role in KSHV viral genome replication, and provide new clues for understanding of KSHV persistence.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), a human oncogenic DNA gammaherpesvirus, is known for its causal association with human cancers, including endothelial-derived Kaposi’s sarcoma (KS), a B cell malignancy named primary effusion lymphoma (PEL), and a plasmablastic form of the B lymphoproliferative disorder named multicentric Castleman disease (MCD) [1,2,3,4]
We find a novel host protein N-Myc downstream regulated gene 1 (NDRG1) is highly up-regulated by KSHV infection and the viral protein latency-associated nuclear antigen (LANA) is essential in this process
Our findings show that NDRG1 functions as a scaffold protein that forms a complex with proliferating cell nuclear antigen (PCNA) and LANA, thereby helping LANA load PCNA onto the viral genome and facilitating the replication and persistence of KSHV
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), a human oncogenic DNA gammaherpesvirus, is known for its causal association with human cancers, including endothelial-derived Kaposi’s sarcoma (KS), a B cell malignancy named primary effusion lymphoma (PEL), and a plasmablastic form of the B lymphoproliferative disorder named multicentric Castleman disease (MCD) [1,2,3,4]. KSHV infection of host cells is predominantly latent, and the virus establishes lifelong persistence of its genome in proliferating cells, which contributes to tumorigenesis. KSHV exists as a circular extrachromosomal episome tethered to the host chromosome [5,6,7,8]. KSHV typically replicates once, accompanied by host replication, and is distributed into daughter cells along with the host chromosomes [5,6,8,9,10,11,12]. KSHV-positive PEL cells, such as BCBL1, BC3, and JSC1, are cultured cell lines established from KSHV-infected PEL samples, and there are multiple copies of viral episomes in these cells, ranging from approximately 50 to 200 per cell. The copy number of the KSHV genome remains constant with cell division, suggesting that there are mechanisms by which KSHV persists in these cells
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