Induction of Kaposi Sarcoma Associated Herpesvirus-encoded Thymidine Kinase (ORF21) by X-Box Binding Protein-1.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Like other herpesviruses, it has latent and lytic repertoires. However, there is evidence that some lytic genes can be directly activated by certain cellular factors. Cells undergoing endoplasmic reticulum stress express spliced X-box binding protein-1 (XBP-1s). XBP-1s is also present in high amounts in germinal center B cells. XBP-1s can activate the KSHV replication and transcription activator (RTA) and lytic replication. It can also directly activate KSHV-encoded viral interleukin-6 (vIL-6) and thus contribute to the pathogenesis of KSHV multicentric Castleman disease (MCD). KSHV thymidine kinase (TK), the ORF21 gene product, can enhance production of thymidine triphosphate and is important for lytic replication. It can also phosphorylate zidovudine and ganciclovir to toxic moieties, enabling treatment of KSHV-MCD with these drugs. We show here that XBP-1s can directly activate ORF21 and that this activation is mediated primarily through two XBP-response elements (XRE) on the ORF21 promoter region. Deletion or mutation of these elements eliminated XBP-1s-induced up-regulation of the promoter, and chromatin immunoprecipitation studies provide evidence that XBP-1s can bind to both XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce ORF21 within 4 hours, and ORF21 expression in the lymph nodes of patients with KSHV-MCD is predominanty found in cells with XBP-1. Thus, XBP-1s may directly upregulate KSHV ORF21 and thus contribute to the pathogenesis of KSHV-MCD and the activity of zidovudine and ganciclovir in this disease.Importance: Spliced X-box binding protein-1 (XBP-1s), part of the unfloded protein response and expressed in developing germinal center B cells, can induce Kaposi sarcoma associated herpesvirus (KSHV) lytic repliction and directly activate viral interleukin-6 (vIL-6). We show here that XBP-1s can also directly activate KSHV ORF21, a lytic gene. ORF21 encodes KSHV thymidine kinase (TK), which increases the pool of thymidine triphosphate for viral replication and enhances lytic replication. Direct activation of ORF21 by XBP-1s can enhance viral replication in germinal center B cells and contribute to the pathogenesis of KSHV multicentric castleman disease (MCD). KSHV-MCD is characterized by systemic inflammation caused in part by lytic replication and overproduction of KSHV vIL-6 in XBP-1s-expressing lymph node plasmablasts. KSHV thymidine kinase can phosphorylate zidovudine and ganciclovir to toxic moieties, and direct activation of ORF21 by XBP-1s may also help explain the effectiveness of zidovudine and valganciclovir in the treatment of KSHV-MCD .