Activation of the Unfolded Protein Response by 2-Deoxy- d -Glucose Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication and Gene Expression

Abstract

Lytic replication of the Kaposi's sarcoma-associated herpesvirus (KSHV) is essential for the maintenance of both the infected state and characteristic angiogenic phenotype of Kaposi's sarcoma and thus represents a desirable therapeutic target. During the peak of herpesvirus lytic replication, viral glycoproteins are mass produced in the endoplasmic reticulum (ER). Normally, this leads to ER stress which, through an unfolded protein response (UPR), triggers phosphorylation of the ␣ subunit of eukaryotic initiation factor 2 (eIF2␣), resulting in inhibition of protein synthesis to maintain ER and cellular homeostasis. However, in order to replicate, herpesviruses have acquired the ability to prevent eIF2␣ phosphorylation. Here we show that clinically achievable nontoxic doses of the glucose analog 2-deoxy-D-glucose (2-DG) stimulate ER stress, thereby shutting down eIF2␣ and inhibiting KSHV and murine herpesvirus 68 replication and KSHV reactivation from latency. Viral cascade genes that are involved in reactivation, including the master transactivator (RTA) gene, glycoprotein B, K8.1, and angiogenesis-regulating genes are markedly decreased with 2-DG treatment. Overall, our data suggest that activation of UPR by 2-DG elicits an early antiviral response via eIF2␣ inactivation, which impairs protein synthesis required to drive viral replication and oncogenesis. Thus, induction of ER stress by 2-DG provides a new antiherpesviral strategy that may be applicable to other viruses.

Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1

“…It has recently been reported by Leung et al that 2-deoxy-D-glucose, a stimulator of ER stress, suppressed KSHV replication and expression of vIL-6 in butyrate-stimulated endothelial or epithelial cells (54). At first glance, these results seem at odds with the current study.…”

“…At first glance, these results seem at odds with the current study. However, Leung et al were looking at a modulation of KSHV induction by butyrate in KSHV-infected endothelial cells and cell lines and note that their findings would probably not apply to B cells, given the substantial expression of XBP-1 during B cell differentiation (54). Thus, these results are not inconsistent although it is possible that the upregulation of RTA and vIL-6 in our PEL cultures exposed to chemical inducers of ER stress was reduced somewhat by that mechanism.…”

MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo

“…Some observations suggest that activation of angiogenesis could be an integral part of the adaptive stress response of cancer cells to viral infection and replication [15,16]. Several anti-angiogenic molecules have been utilized to augment the therapeutic effect of oncolytic vectors by suppressing tumor angiogenesis [17].…”

Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway

“…For infection studies, adherent HEK293 cells were infected with rKSHV.219 under puromycin selection as described previously 42,68 . For lytic induction, rKSHV.219-infected HEK293 cells were treated at 70% confluence with 3mM sodium butyrate.…”