Epstein–Barr virus-encoded protein kinase BGLF4 mediates hyperphosphorylation of cellular elongation factor 1δ (EF-1δ): EF-1δ is universally modified by conserved protein kinases of herpesviruses in mammalian cells

Kato, Kentaro; Kawaguchi, Yasushi; Tanaka, Michiko; Igarashi, Mie; Yokoyama, Akihiko; Matsuda, Go; Kanamori, Mikiko; Nakajima, Kiyokazu; Nishimura, Yorihiro; Shimojima, Masayuki; Phung, Hang Thi Thu; Takahashi, Eiji; Hirai, Kanji

doi:10.1099/0022-1317-82-6-1457

Cited by 70 publications

(41 citation statements)

References 32 publications

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“…BGLF4 kinase is a virion-associated serine/ threonine kinase expressed during the early and late stages of the lytic cycle (55). Several viral proteins expressed at different stages of virus replication have been shown to be phosphorylated by BGLF4, including EBNA2, EBNA-LP, BMRF1, BZLF1, viral DNA replication proteins, and structural components (3,26,27,61,65,66). In cells replicating EBV, BGLF4 colocalizes with the viral DNA polymerase processivity factor BMRF1 in the viral DNA replication compartment and phosphorylates BMRF1 at multiple sites in vitro and in vivo (55,61).…”

Section: E Pstein-barr Virus (Ebv) Is a Ubiquitous Gammaherpesvirus Tmentioning

confidence: 99%

Epstein-Barr Virus Protein Kinase BGLF4 Targets the Nucleus through Interaction with Nucleoporins

Chang

Lee

Huang

et al. 2012

J Virol

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bBGLF4 of Epstein-Barr virus (EBV) encodes a serine/threonine protein kinase that phosphorylates multiple viral and cellular substrates to optimize the cellular environment for viral DNA replication and the nuclear egress of viral nucleocapsids. BGLF4 is expressed predominantly in the nucleus at early and late stages of virus replication, while a small portion of BGLF4 is distributed in the cytoplasm at the late stage of virus replication and packaged into the virion. Here, we analyzed systematically the functional domains crucial for nuclear localization of BGLF4 and found that both the N and C termini play important modulating roles. Analysis of amino acid substitution mutants revealed that the C terminus of BGLF4 does not contain a conventional nuclear localization signal (NLS). Additionally, deletion of the C-terminal putative helical regions at amino acids 386 to 393 and 410 to 419 diminished the nuclear translocation of BGLF4, indicating that the secondary structure of the C terminus is important for the localization of BGLF4. The green fluorescent protein-fused wild-type or C-terminal helical regions of BGLF4 associate with phenylalanine/glycine repeat-containing nucleoporins (Nups) in nuclear envelope fractionation. Both coimmunoprecipitation and in vitro pull-down assays further demonstrated that BGLF4 binds to Nup62 and Nup153. Remarkably, nuclear import assay with permeabilized HeLa cells demonstrated that BGLF4 translocated into nucleus independent of cytosolic factors. Data presented here suggest that BGLF4 employs a novel mechanism through direct interactions with nucleoporins for its nuclear targeting. E pstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that infects most of the human population worldwide (64).Upon stimulation of various kinds, the latent virus may be reactivated through expression of the viral immediate-early transactivators Zta and Rta, which then turn on the expression cascade of viral genes (39, 41). BGLF4 kinase is a virion-associated serine/ threonine kinase expressed during the early and late stages of the lytic cycle (55). Several viral proteins expressed at different stages of virus replication have been shown to be phosphorylated by BGLF4, including EBNA2, EBNA-LP, BMRF1, BZLF1, viral DNA replication proteins, and structural components (3,26,27,61,65,66). In cells replicating EBV, BGLF4 colocalizes with the viral DNA polymerase processivity factor BMRF1 in the viral DNA replication compartment and phosphorylates BMRF1 at multiple sites in vitro and in vivo (55,61). BGLF4 phosphorylates the cellular replication origin binding complex MCM4-MCM6-MCM7, leading to inhibition of its helicase activities (31). Our study also indicated that BGLF4 recruits the cellular nucleotide excision repair protein XPC to the viral replication compartment to enhance viral DNA replication (40). Expression of BGLF4 alone in transfected cells induces premature chromosome condensation through the activation of condensin and topoisomerase II (33). Most importantly, small interfering RNA expe...

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Section: E Pstein-barr Virus (Ebv) Is a Ubiquitous Gammaherpesvirus Tmentioning

confidence: 99%

Epstein-Barr Virus Protein Kinase BGLF4 Targets the Nucleus through Interaction with Nucleoporins

Chang

Lee

Huang

et al. 2012

J Virol

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“…For example, tyrosine phosphorylation of specific residues within Src-family kinases is required for Src to interaction with proteins carrying SH2 domains (Pawson, 1995;Thomas and Brugge, 1997). For herpesvirus, in addition to HCMV UL97 (He et al, 1997) and HSV-1 UL13 (Cunningham et al, 1992), EBV encoded BGLF4 has also presented an ability to autophosphorylate itself (Kato et al, 2001), albeit the full effects of these autophosphorylations on protein activity remains to be further investigation. Moreover, it is still unknown whether autophosphorylation of viral kinases will induce the same effect, such as regulating catalytic activity and recruiting other proteins for interaction, as the autophosphorylation of cellular kinases.…”

Section: Viral Proteins Is Phosphorylated By Cellular and Viral Kinasesmentioning

confidence: 99%

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

et al. 2017

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Activation of specific sets of protein kinases by intracellular signal molecules has become more and more apparent in the past decade. Phosphorylation, one of key posttranslational modification events, is activated by kinase or regulatory protein and is vital for controlling many physiological functions of eukaryotic cells such as cell proliferation, differentiation, malignant transformation, and signal transduction mediated by external stimuli. Moreovers, the reversible modification of phosphorylation and dephosphorylation can result in different features of the target substrate molecules including DNA binding, protein-protein interaction, subcellular location and enzymatic activity, and is often hijacked by viral infection. Epstein-Barr virus (EBV) and Kaposi's sarcomaassociated herpesvirus (KSHV), two human oncogenic gamma-herpesviruses, are shown to tightly associate with many malignancies. In this review, we summarize the recent progresses on understanding of molecular properties and regulatory modes of cellular and viral proteins phosphorylation influenced by these two tumor viruses, and highlight the potential therapeutic targets and strategies against their related cancers.

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“…The BGLF4 phosphorylation of cellular elongation factor 1-␦ (EF1-␦) may play a role in viral protein translation (54,56). The phosphorylation of MCM4 by BGLF4 blocks host chromosomal DNA replication in the infected cells (60).…”

Section: Pstein-barr Virus (Ebv) First Discovered In Association Withmentioning

confidence: 99%

SUMO Binding by the Epstein-Barr Virus Protein Kinase BGLF4 Is Crucial for BGLF4 Function

Wang

Liao

et al. 2012

J Virol

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E pstein-Barr virus (EBV), first discovered in association withBurkitt's lymphoma (27), is linked to a variety of human diseases, including infectious mononucleosis, nasopharyngeal carcinoma, gastric carcinoma, and posttransplant lymphoproliferative disease (105). EBV infection results in either lytic replication or the establishment of viral latency. Both latent and lytic EBV gene products have been implicated in the development of cancer (28,51,72,105). EBV can be reactivated from latency by various reagents, such as 5-bromodeoxyuridine (39, 46), phorbol esters (110), anti-Ig antibodies (23,92,97), sodium butyrate (71), methotrexate (28), bortezomib (33, 34), thapsigargin (88, 95), and arsenic trioxide (89). The transition from latency to lytic replication is mediated by two EBV immediate-early genes, BZLF1 and BRLF1. The encoded proteins, ZTA and RTA, function as transcriptional activators that regulate the expression of EBV lytic cycle genes and lytic viral DNA replication (16,21,22,31,36,69,70,83,86,96). The lytic induction of EBV has been postulated as a therapeutic strategy for the treatment of virus-associated tumors (29,30,33,77).The small ubiquitin-related modifier (SUMO) was first identified as a posttranslational modifier of RanGAP1 (73,75). Similarly to the ubiquitination pathway, SUMOylation involves a series of sequential enzymatic reactions. The SUMO precursor protein is first cleaved by sentrin-specific proteases (SENPs) to generate a C-terminal diglycine motif. This then forms an E1ϳSUMO thioester, which is transferred to the E2-conjugating enzyme UBC9. E2ϳSUMO directly transfers SUMO to the substrate at lysine residues to form an isopeptide bond. E3 SUMO protein ligases facilitate this process by recruiting E2ϳSUMO to specific substrates and by enhancing the transfer process. SUMOylated targets can be de-SUMOylated by the SENP removal of SUMO (37). SUMOylation has been implicated in a variety of cellular processes, including transcriptional regulation, cell cycle regulation, signal transduction, the DNA damage response (DDR), and the regulation of protein-protein interactions (38). Both latent and lytic EBV proteins interact with the SUMO system. EBNA3C is SUMOylated (84), while LMP1 modulates the SUMOylation processes by interaction with UBC9 (6). SUMOylation regulates the transcriptional activity of ZTA and RTA (10,13,14,45,47,80). Noncovalent SUMO-protein interactions can also occur through a SUMO interaction motif (SIM) in the target proteins (3,57,90,91,93). EBNA3C contains a SIM motif and upregulates EBNA2-mediated gene activation by binding to a SUMOylated protein (84).In this study, we used an EBV protein microarray to identify additional EBV proteins that bind to SUMO. One of the identified proteins was the conserved protein kinase BGLF4. BGLF4 is present in the virion and expressed at an early stage of the lytic cycle (40,41,99). BGLF4 phosphorylates multiple EBV proteins, including BMRF1 (18, 42), EBNA2 (106), EBNA-LP (55), ZTA (4), EBNA1, and virion proteins (108). BGLF4 also phosp...

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Epstein–Barr virus-encoded protein kinase BGLF4 mediates hyperphosphorylation of cellular elongation factor 1δ (EF-1δ): EF-1δ is universally modified by conserved protein kinases of herpesviruses in mammalian cells

Cited by 70 publications

References 32 publications

Epstein-Barr Virus Protein Kinase BGLF4 Targets the Nucleus through Interaction with Nucleoporins

Epstein-Barr Virus Protein Kinase BGLF4 Targets the Nucleus through Interaction with Nucleoporins

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

SUMO Binding by the Epstein-Barr Virus Protein Kinase BGLF4 Is Crucial for BGLF4 Function

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