Cellular STAT3 Functions via PCBP2 To Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes

Koganti, Siva; Clark, Carissa; Zhi, Jizu; Li, Xiaofan; Chen, Emily I.; Chakrabortty, Sharmistha; Hill, Emily B.; Bhaduri‐McIntosh, Sumita

doi:10.1128/jvi.00121-15

Cited by 37 publications

(32 citation statements)

References 42 publications

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“…This study and our earlier studies demonstrate that, in addition to phosphorylation and dimerization of STAT3, modulation of the protein level of STAT3 also regulates its function (22,30,(37)(38)(39). Our data also indicate that STAT3 functions at least partly by repressing the immediate-early gene product RTA, the key latency-to-lytic-phase viral switch.…”

Section: Discussionsupporting

confidence: 59%

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

King

Barbachano-Guerrero

et al. 2015

J Virol

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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...

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Section: Discussionsupporting

confidence: 59%

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

King

Barbachano-Guerrero

et al. 2015

J Virol

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“…Activity of the BZLF1 promoter is determined by a balance of positive and negative transcription factors that epigenetically mediate activating and silencing marks on histones. Examples of positive transcription factors include CREB, ATF, AP-1, EBP, ZBP1, and MEF2, while ZEB1, ZEB2, KRAB-ZFPs, KAP1, and STAT3 are negative regulators (5,24,26,(37)(38)(39). If EBV switches into the lytic phase, the switch, i.e., ZEBRA, must remain on for successful production of infectious particles.…”

Section: Discussionmentioning

confidence: 99%

Retrograde Regulation by the Viral Protein Kinase Epigenetically Sustains the Epstein-Barr Virus Latency-to-Lytic Switch To Augment Virus Production

Kozlov

El-Guindy

et al. 2019

J Virol

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Herpesviruses are ubiquitous, and infection by some, like Epstein-Barr virus (EBV), is nearly universal. To persist, EBV must periodically switch from a latent to a replicative/lytic phase. This productive phase is responsible for most herpesvirus-associated diseases. EBV encodes a latency-to-lytic switch protein which, upon activation, sets off a vectorially constrained cascade of gene expression that results in production of infectious virus. While triggering expression of the switch protein ZEBRA is essential to lytic cycle entry, sustaining its expression is equally important to avoid premature termination of the lytic cascade. We report that the viral protein kinase (vPK), encoded by a gene that is kinetically downstream of the lytic switch, sustains expression of ZEBRA, amplifies the lytic cascade, increasing virus production, and, importantly, prevents the abortive lytic cycle. We find that vPK, through a noncanonical site phosphorylation, activates the cellular phosphatidylinositol 3-kinase-related kinase ATM to cause phosphorylation of the heterochromatin enforcer KAP1/TRIM28 even in the absence of EBV genomes or other EBV proteins. Phosphorylation of KAP1 renders it unable to restrain ZEBRA, thereby further derepressing and sustaining its expression to culminate in virus production. This partnership with a host kinase and a transcriptional corepressor enables retrograde regulation by vPK of ZEBRA, an observation that is counter to the unidirectional regulation of gene expression reminiscent of most DNA viruses. IMPORTANCE Herpesviruses infect nearly all humans and persist quiescently for the life of the host. These viruses intermittently activate into the lytic phase to produce infectious virus, thereby causing disease. To ensure that lytic activation is not prematurely terminated, expression of the virally encoded lytic switch protein needs to be sustained. In studying Epstein-Barr virus, one of the most prevalent human herpesviruses that also causes cancer, we have discovered that a viral kinase activated by the viral lytic switch protein partners with a cellular kinase to deactivate a silencer of the lytic switch protein, thereby providing a positive feedback loop to ensure successful completion of the viral productive phase. Our findings highlight key nodes of interaction between the host and virus that could be exploited to treat lytic phase-associated diseases by terminating the lytic phase or kill cancer cells harboring herpesviruses by accelerating the completion of the lytic cascade.

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“…They found that various signaling pathways including ATM, p38 and JNKs are activated by ROS and involved in the induction of EBV reactivation in a p53-dependent manner. Also, phosphorylation of the ATF2 transcription factor by p38 and JNKs has been reported to activate Zp 16, implying deregulated ROS signaling might similarly induce EBV reactivation from latency through modification of other redox-sensitive transcription factors that activate Zp and/or Rp, such as early growth response 1 (EGR1) 54,55, Sp1 56, Stat3 57, and c-Jun 58.…”

Section: Host Factors Contributing To the Regulation Of Ebv Reactimentioning

confidence: 99%

Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis

Li¹,

Liu²,

Hu³

et al. 2016

Int. J. Biol. Sci.

106

111

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Epstein-Barr virus (EBV) has been associated with several types of human cancers. In the host, EBV can establish two alternative modes of life cycle, known as latent or lytic and the switch from latency to the lytic cycle is known as EBV reactivation. Although EBV in cancer cells is found mostly in latency, a small number of lytically-infected cells promote carcinogenesis through the release of growth factors and oncogenic cytokines. This review focuses on the mechanisms by which EBV reactivation is controlled by cellular and viral factors, and discusses how EBV lytic infection contributes to human malignancies.

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Cellular STAT3 Functions via PCBP2 To Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes

Cited by 37 publications

References 42 publications

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

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

Retrograde Regulation by the Viral Protein Kinase Epigenetically Sustains the Epstein-Barr Virus Latency-to-Lytic Switch To Augment Virus Production

Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis

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