Persistent Activation of STAT3 by Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells

Punjabi, Almira S.; Carroll, Patrick A.; Chen, Lei; Lagunoff, Michael

doi:10.1128/jvi.01769-06

Cited by 66 publications

(85 citation statements)

References 52 publications

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“…Constitutive expression of pSTAT3 and survivin is a wellknown characteristic of tumor cells and cells transformed by oncogenic viruses, including KSHV and EBV (14,(26)(27)(28). Our study of VZV shows that STAT3 activation and survivin expression also support lytic herpesvirus replication not only in vitro but also in differentiated human skin cells within their tissue microenvironment in vivo.…”

Section: Discussionmentioning

confidence: 80%

“…STAT3 activation leads to overexpression of genes involved in tumorigenesis and is constitutive in most primary human tumors (11)(12)(13). STAT3 plays a significant role in the pathogenesis of the γ-herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV), and herpesvirus saimiri (14)(15)(16), all of which exploit the oncogenic effects of phosphorylated STAT3 (pSTAT3).…”

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confidence: 99%

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Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.T he life cycle of varicella-zoster virus (VZV) in the human host depends on its tropism for T cells, skin, and neurons within sensory ganglia (1). As shown in the SCID mouse model of VZV pathogenesis, infected human T cells transport the virus to epidermal cells in human skin xenografts and to neural cells in dorsal root ganglia xenografts (2, 3). VZV establishes latency in sensory ganglia; upon reactivation, the virus migrates to the skin via axonal transport to cause zoster.VZV modulates several signaling pathways to replicate efficiently in vitro, and these regulatory effects are especially important in differentiated skin cells infected in vivo. VZV interferes with IFN induction and signaling via inhibition of IFN regulatory factor 3 (IRF3), NFκB, and STAT1 in vitro and in skin (4, 5). However, the pathogenesis of VZV skin infection requires a mechanism to overcome the constitutive IFNα expression by epidermal cells that accounts for the 10-to 21-d interval between VZV transfer into skin and the appearance of lesions at skin surfaces (6). How VZV overcomes this cutaneous IFN barrier and produces skin vesicles is not known.The STATs are ubiquitous transcription factors with many cellular functions and are at the junction of several cytokinesignaling pathways (7,8). Of the seven STAT family proteins, STAT3 exerts widespread effects through transcri...

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…KSHV inoculum from induced BCBL-1 cells was tittered and used to infect TIME and 1°hDMVECs as previously described (31). All cells were infected in serum-free EBM-2 or DMEM media for 3.5 h, after which the medium was replaced with complete EGM-2 or DMEM media.…”

Section: Methodsmentioning

confidence: 99%

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Delgado

Carroll

Punjabi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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211

233

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Kaposi's sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.human herpesvirus-8 | gamma-herpesvirus | latency | glycolysis

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“…STAT3 is constitutively activated in some KSHV-positive PEL cell lines, and expression of a dominant-negative form of STAT3 induces apoptosis in PEL cells (29). Latently infected telomerase reverse transcriptase (TERT)-immortalized endothelial cells display persistent activation of STAT3 (30); however, the role of STAT3 in primary endothelial cells, the major in vivo target of KSHV, is unclear. Despite the importance of STAT3 in inflammation and tumorigenesis, our understanding of the mechanisms governing STAT3 transcriptional activation in primary endothelial cells during KSHV infection remains incomplete.…”

mentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

King

2013

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1␤), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.

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Persistent Activation of STAT3 by Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells

Cited by 66 publications

References 52 publications

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

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