The Latent Membrane Protein 1 of Epstein-Barr Virus (EBV) Primes EBV Latency Cells for Type I Interferon Production

Xu, Dongsheng; Brumm, Kristen; Zhang, Luwen

doi:10.1074/jbc.m511884200

Cited by 42 publications

(46 citation statements)

References 71 publications

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“…EBV LMP-1 has been shown to suppress EBV reactivation triggered by either anti-immunoglobulin M or TPA (3,63). In addition, we have shown that LMP-1 is an antiviral protein (87,90). These published results suggest that LMP-1 might inhibit the lytic replication of KSHV.…”

Section: Ebv Inhibits Lytic Replication Of Kshvmentioning

confidence: 55%

Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas

Xu¹,

Coleman²,

Zhang³

et al. 2007

J Virol

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virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8, are members of the human gammaherpesviruses and are associated with a variety of human malignancies. EBV is an important cause of lymphomas in severely immunocompromised persons, especially patients with AIDS and organ-transplant recipients (46,61,62,64,66). KSHV is believed to be the etiological agent of Kaposi's sarcoma (16,18,60) and is implicated in the pathogenesis of AIDS-associated primary effusion lymphoma (PEL), also called body cavity-based lymphoma, and multicentric Castleman's disease (23,60,86).Like other herpesviruses, EBV and KSHV go through both latency and lytic replication cycles. The KSHV replication and transcription activator (K-RTA) is necessary and sufficient for the switch from latency to lytic replication in KSHV (23,86,88). K-RTA is a sequence-specific DNA-binding protein that regulates many subsequently expressed viral genes (38,56,69,70,75,91,97). Also, K-RTA can interact with other factors to modulate its transcription potential (39,40,(51)(52)(53).EBV latent membrane protein 1 (LMP-1) is required for EBV transformation of primary B cells and establishment of EBV latency in vitro and is believed to play similar roles in EBV-associated tumor cells in vivo (45, 47). LMP-1 is an integral membrane protein and acts as a constitutively active receptor-like molecule that does not need a ligand (30,36,46,54). LMP-1 activates a variety of cellular genes that enhance cell survival and adhesive, invasive, angiogenic, and antiviral potential (31, 41, 59, 81-83, 87, 90, 94, 95).Interestingly, the majority of PELs are harboring both EBV and KSHV (13,14,42,68). In order to understand their contributions to the pathogenesis of PEL, it is important to address how EBV and KSHV interact with each other and affect biological properties of the cell and the viruses. PELs harboring two viruses have higher oncogenic potential (76), suggesting potential interactions between EBV and KSHV. This report describes a molecular interaction between EBV and KSHV, i.e., KSHV K-RTA potentiates EBV latency via induction of EBV LMP-1 and uses LMP-1 to curb KSHV lytic replication. These data suggest that the coinfection of EBV and KSHV in the majority of body cavity-based lymphomas might not be a coincidence: the presence of EBV is one of the strategies that KSHV uses for the maintenance of its latency. This report should be applicable to both KSHV and EBV studies in the majority of AIDS-associated PELs. MATERIALS AND METHODSCell culture, plasmids, adenoviruses, and antibodies. All cell lines used in this study and their properties are listed in Table 1. Expression plasmids for K-RTA (pCMV50) and the recombinant adenoviruses for green fluorescence protein (GFP) (AdGFP) and K-RTA (AdRTA) were a gift from Byrd Quinlivan (71).

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Section: Ebv Inhibits Lytic Replication Of Kshvmentioning

confidence: 55%

Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas

Xu¹,

Coleman²,

Zhang³

et al. 2007

J Virol

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“…For example, although V protein of parainfluenza 5 antagonizes IFN response by degrading STAT1, appropriate IFNs may change the pattern of viral transcription and protein synthesis, and thus facilitate the establishment of persistent infections (52)(53)(54). SM protein of EBV during the lytic cycle inhibits protein kinase R activation, whereas EBV LMP-1 protein can prime EBV latency cells for IFN production to establish the viral latency (55)(56)(57). Recent studies have demonstrated that HBoV can establish persistent infection in host cells by forming episomes (58).…”

Section: Discussionmentioning

confidence: 99%

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Luo

Zhang

Zheng

et al. 2013

The Journal of Immunology

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Precise regulation of innate immunity is crucial for maintaining optimal immune responses against infections. Whereas positive regulation of IFN signaling elicits rapid type I IFNs, negative regulation is equally important in preventing the production of superfluous IFNs that can be hazardous to the host. The positive regulators of IFN pathway are known to be the main targets of viruses to antagonize the innate immune system. Whether viruses target the negative regulators of IFN pathway remains to be fully investigated. In this study, we report that the structural protein VP2 of human Bocavirus modulates IFN pathway by targeting the ring finger protein 125 (RNF125), a negative regulator of type I IFN signaling, which conjugates Lys48-linked ubiquitination to retinoic acid–inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. VP2 not only upregulated Sendai virus (SeV)–induced IFNB promoter activity, but also enhanced SeV-induced IFN-β production at both mRNA and protein levels. In agreement, the level of Ser396-phosphorylated IFN regulatory factor 3 stimulated by SeV was enhanced in the presence of VP2. Furthermore, VP2 was demonstrated to physically interact with RNF125, resulting in the reduction of RNF125-mediated ubiquitination and proteasome-dependent degradation of RIG-I. Additional study indicated that endogenous RIG-I degradation was decreased in VP2-expressing cells. Our study delineates a unique phenomenon for aberrant activation of IFN regulatory factor 3 pathway and may represent a new mechanism underlying viral manipulation of the host immune system.

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“…Since the stimuli are diverse, the mechanisms that govern the activity of IRF7 are likely to be complex and are important to understand. We have However, IRF7's role may be in priming of latently EBVinfected cells by LMP1 for IFN production, the effect of which is to inhibit lytic EBV replication and superinfection by other viruses and thus to avert disruption of latency (42). Maintenance of latency is important for viral persistence because EBV, particularly the lytic antigens, generates robust cytotoxic-T-cell responses (30).…”

Section: Discussionmentioning

confidence: 99%

“…IRF7 is necessary for LMP1-induced up-regulation of Tap-2 expression (45) and has been implicated in LMP1-mediated priming of EBV latently infected cells for production of type I IFN (42). In this study, we examine LMP1 signaling events that lead to the activation of IRF7.…”

mentioning

confidence: 99%

Interferon Regulatory Factor 7 Is Activated by a Viral Oncoprotein through RIP-Dependent Ubiquitination

Huye

Ning

Kelliher

et al. 2007

Molecular and Cellular Biology

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As a key mediator of type I interferon (IFN) (IFN-␣/␤) responses, IFN regulatory factor 7 (IRF7) is essential to host immune defenses. Activation of IRF7 generally requires virus-induced C-terminal phosphorylation, which leads to its nuclear accumulation and activation of target genes. Here we use the Epstein-Barr virus (EBV) oncoprotein LMP1, which activates IRF7, to identify factors involved in IRF7 activation. We demonstrate for the first time that RIP activates IRF7 and that RIP and IRF7 interact under physiological conditions in EBV-positive Burkitt's lymphoma cells. We provide evidence that both RIP and IRF7 are ubiquitinated in these cells and that IRF7 preferentially interacts with ubiquitinated RIP. RIP is required for full activation of IRF7 by LMP1, with LMP1 stimulating the ubiquitination of RIP and its interaction with IRF7. Moreover, LMP1 stimulates RIP-dependent K63-linked ubiquitination of IRF7, which regulates protein function rather than proteasomal degradation of proteins. We suggest that RIP may serve as a general activator of IRF7, responding to and transmitting the signals from various stimuli, and that ubiquitination may be a general mechanism for enhancing the activity of IRF7.

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The Latent Membrane Protein 1 of Epstein-Barr Virus (EBV) Primes EBV Latency Cells for Type I Interferon Production

Cited by 42 publications

References 71 publications

Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas

Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas

Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I

Interferon Regulatory Factor 7 Is Activated by a Viral Oncoprotein through RIP-Dependent Ubiquitination

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