STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

Abstract

Lytic activation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency is a critical contributor to pathogenesis and progression of KSHV-mediated disease. Development of targeted treatment strategies and improvement of lytic-phase-directed oncolytic therapies, therefore, hinge on gaining a better understanding of latency-to-lytic-phase transition. A key observation in that regard, also common to other herpesviruses, is the partial permissiveness of latently infected cells to lytic-cycle-inducing agents. Here, we address the molecular basis of why only some KSHV-infected cells respond to lytic stimuli. Since cellular signal transducer and activator of transcription 3 (STAT3) is constitutively active in KSHV-associated cancers, KSHV activates STAT3, and STAT3 has been found to regulate lytic activation of Epstein-Barr virus (EBV)-infected cells, we asked if STAT3 contributes similarly to the life cycle of KSHV. We found that high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. Further, knockdown of STAT3 suppresses the cellular transcriptional corepressor Krüppel-associated box domain-associated protein 1 (KAP1; also known as TRIM28), and suppression of KAP1 activates lytic genes, including the viral lytic switch RTA, thereby linking STAT3 via KAP1 to regulation of the balance between lytic and latent cells. These findings, taken together with those from EBV-infected and, more recently, herpes simplex virus 1 (HSV-1)-infected cells, cement the contribution of host STAT3 to persistence of herpesviruses and simultaneously reveal an important lead to devise strategies to improve lytic-phasedirected therapies for herpesviruses. IMPORTANCELytic activation of the cancer-causing Kaposi's sarcoma-associated herpesvirus (KSHV) is vital to its life cycle and causation of disease. Like other herpesviruses, however, a substantial fraction of latently infected cells are resistant to lytic-phase-inducing stimuli. Investigating the molecular basis for this refractory state is essential for understanding how the virus persists and how it causes disease and to guide efforts to improve treatment of KSHV-mediated diseases. We found that, like two other herpesviruses, EBV and HSV-1, KSHV exploits the cellular transcription factor STAT3 to regulate the susceptibility of latently infected cells to lytic triggers. These findings highlight a common STAT3-centered strategy used by herpesviruses to maintain persistence in their hosts while also revealing a key molecule to pursue while devising methods to improve herpesvirus lytic-phase-directed therapies.T he oncogenic human gammaherpesvirus human herpesvirus 8 (HHV-8), widely known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of three human malignancies: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). Like other herpesviruses, KSHV exhi...

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

“…Interestingly, inhibition of STAT3 activation promoted HIV-1 Tat-dependent KSHV lytic reactivation56, supporting our observations that STAT3 may function as an inhibitor of the lytic cycle. A recent study showed that inhibition of STAT3 in PEL cells enhances KSHV lytic replication and correlates with our findings57. We have also extended this to further demonstrate a potential strategy for elimination of latent cells using a combination of a STAT3 inhibitor and ganciclovir (Fig.…”

Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency

“…The control of the latent and lytic phases of herpesviruses is a complex interplay and orchestration between viral and host factors. Host factors such as STAT3 (21), KAP1/TRIM28 (22), retinoblastoma (Rb) (23), and the cellular peptidyl-prolyl cis/trans isomerase Pin1 (24) were recently found to play very important roles in this latent-tolytic life cycle switch of herpesviruses.…”

Epigenetics and Genetics of Viral Latency

“…KAP1 restricts HIV1 integration (Allouch et al, 2011), and maintains latency for KSHV (Cai et al, 2013; Gjyshi et al, 2015; King et al, 2015; Sun et al, 2014; Zhang et al, 2014), EBV (Bentz et al, 2015), and HCMV (Rauwel et al, 2015). Phosphorylation of KAP1 decreases its ability to induce heterochromatin and triggers reactivation of HCMV (Rauwel et al, 2015).…”

“…The LANA-KAP1 complex was found to associate with the viral immediate early control region upstream of the viral immediate early transcriptional activator (RTA) gene (Sun et al, 2014) and regulate the hypoxia response pathway mediated by the transcriptional regulators HIF1α and RBP-jK (Zhang et al, 2014). Modulation of the KAP1 pathway by the transcription factors NRF2 (Gjyshi et al, 2015), and STAT3 (King et al, 2015) also contribute to KSHV latent to lytic switch, further highlighting the central role of KAP1 in regulating viral latency.…”