Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies. KSHV vCyclin contributes to KSHV latency by promoting cell cycle progression and proliferation, but the regulation and posttranslational modifications (PTMs) of vCyclin have not been fully elucidated. Here, we report that PRMT5, a novel vCyclin binding partner, is significantly upregulated by LANA. Importantly, PRMT5 methylates vCyclin symmetrically and stabilizes vCyclin in a methyltransferase activity-dependent manner, thereby promoting cell cycle progression and proliferation of KSHV latently infected tumor cells. We also report that the methylation of vCyclin positively regulates the pRB pathway. Taken together, the findings indicate that PRMT5 plays an essential role in regulating vCyclin to facilitate cell cycle progression and proliferation and may serve as a therapeutic target for KSHV-associated diseases.