Epstein-Barr Virus Immediate-Early Protein Zta Co-Opts Mitochondrial Single-Stranded DNA Binding Protein To Promote Viral and Inhibit Mitochondrial DNA Replication

Wiedmer, Andreas; Wang, Pu; Zhou, Jing; Rennekamp, Andrew J.; Tiranti, Valeria; Zeviani, Massimo; Lieberman, Paul M.

doi:10.1128/jvi.02198-07

Cited by 47 publications

(45 citation statements)

References 53 publications

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“…To elucidate how Zta activates transcription, MALDI-TOF mass spectrometry was performed and Ku80 was found to interact with His-Zta fusion protein bound to Ni 2+ -charged beads (data not shown). This verifies the results of Wiedmer et al (2008) and Bailey et al (2009), who showed that Ku80 is a binding partner of, and is co-purified with, Zta. Therefore, these results motivated us to investigate the interaction between the two proteins and how the interaction affects the function of Zta.…”

supporting

confidence: 78%

“…Earlier studies performed MALDI-TOF mass spectrometric analysis and demonstrated that Ku80 was co-purified with Zta from ZKO-293 and HEK cells (Bailey et al, 2009;Wiedmer et al, 2008), suggesting that these two proteins interact. Our studies also confirmed that Ku80 co-purified with histidinetagged Zta by using Ni 2+ -charged beads (Qiagen) and MALDI-TOF mass spectrometry (data not shown).…”

Section: Analysing the Interaction Between Zta And Ku80mentioning

confidence: 99%

“…Also, Ku is a co-activator of androgen receptor (AR) and thereby enhances AR-dependent transcription (Mayeur et al, 2005). An earlier immunopurification study revealed that Ku80 is a binding partner of Zta (Wiedmer et al, 2008). Furthermore, Ku80 was co-purified with Zta by using a global tandem affinity purification approach (Bailey et al, 2009).…”

mentioning

confidence: 99%

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Enhancement of Zta-activated lytic transcription of Epstein-Barr virus by Ku80

Chen

Yang

Wang

et al. 2010

Journal of General Virology

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Zta, encoded by the BZLF1 gene of Epstein-Barr virus (EBV), is a transcription factor that is expressed during the immediate-early stage of the lytic cycle. The expression of Zta is crucial to viral lytic development. Earlier studies showed that Ku80 is a binding partner of Zta in ZKO-293 cells and is co-purified with Zta. This study verifies the interaction between Ku80 and Zta by using glutathione S-transferase-pull-down and co-immunoprecipitation assays, and also by indirect immunofluorescence analysis. This investigation also reveals that Ku80 binds to Zta on Ztaresponse elements in the BHLF1 promoter, enhancing the promoter activity. This study also reveals that the interaction between Zta and Ku80 involves the C-terminal region of Zta and the 425 aa N-terminal region of Ku80. The interaction between these two proteins and the enhancement of transcription that is activated by Zta suggest that Ku80 is important to EBV lytic development. INTRODUCTIONWhen Epstein-Barr virus (EBV) enters the lytic cycle, the virus expresses two transcription factors, Rta and Zta (R transactivator and Z transactivator), which are encoded by the BRLF1 and BZLF1 genes, respectively, to activate the transcription of the EBV lytic genes (Speck et al., 1997). Zta is a transcription factor of the bZIP family (Farrell et al., 1989), which activates EBV lytic genes via binding to Ztaresponse elements (ZRE) in promoters (Lieberman & Berk, 1990). Such binding autoregulates the transcription of its own gene, BZLF1 (Flemington & Speck, 1990), and promotes the transcription of another immediate-early gene, BRLF1 (Sinclair et al., 1991). Zta also binds to the ZRE in the origin of lytic replication (oriLyt), which is required for the initiation of lytic DNA replication (Schepers et al., 1993). Additionally, Zta interacts with c-Myb, transcription factor IID (TFIID) and cAMP response element (CREB)-binding protein to activate the expression of EBV early genes (Adamson & Kenney, 1999; Kenney et al., 1992;Lieberman & Berk, 1991). Since the transcription of many EBV lytic genes depends on Zta, EBV cannot complete its lytic cycle without Zta (Chiu et al., 2007;Feederle et al., 2000).Ku, a heterodimeric protein that comprises 70 kDa (Ku70) and 80 kDa (Ku80) subunits, is an autoantigen, which is recognized by the sera of patients with autoimmune disorders (Mimori et al., 1981). The Ku heterodimer is a component of the DNA-dependent protein kinase (DNA-PK) complex, on which the non-homologous end-joining repair of DNA double-strand breaks (DSB) depends . In addition to having a welldocumented role in DSB repair, Ku maintains telomere integrity and promotes apoptosis, V(D)J recombination and DNA replication (Chai et al., 2002;Nussenzweig et al., 1996;Pergola et al., 1993;Tuteja & Tuteja, 2000). Ku also regulates transcription (Hoff & Jacob, 1993;Kuhn et al., 1993;Niu & Jacob, 1994; Nolens et al., 2009;Ohno et al., 2009). An earlier study revealed that Ku recruits DNA-PK to negative regulatory element 1 in LTR to inhibit mouse mammary tumor virus transc...

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supporting

confidence: 78%

Section: Analysing the Interaction Between Zta And Ku80mentioning

confidence: 99%

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Enhancement of Zta-activated lytic transcription of Epstein-Barr virus by Ku80

Chen

Yang

Wang

et al. 2010

Journal of General Virology

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“…4A). Following infection with Epstein-Barr virus, this protein has been shown to be relocalized to the nucleus, where it stimulates viral replication (84). Surprisingly, however, the protein was not detected by immunofluorescence in the nuclei of either infected or transfected HeLaAAVtCR cells ( Table 2).…”

mentioning

confidence: 79%

Identification of Rep-Associated Factors in Herpes Simplex Virus Type 1-Induced Adeno-Associated Virus Type 2 Replication Compartments

Nicolas

Alazard-Dany

Biollay

et al. 2010

J Virol

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Adeno-associated virus (AAV) is a human parvovirus that replicates only in cells coinfected with a helpervirus, such as adenovirus or herpes simplex virus type 1 (HSV-1). We previously showed that nine HSV-1 factors are able to support AAV rep gene expression and genome replication. To elucidate the strategy of AAV replication in the presence of HSV-1, we undertook a proteomic analysis of cellular and HSV-1 factors associated with Rep proteins and thus potentially recruited within AAV replication compartments (AAV RCs). This study resulted in the identification of approximately 60 cellular proteins, among which factors involved in DNA and RNA metabolism represented the largest functional categories. Validation analyses indicated that the cellular DNA replication enzymes RPA, RFC, and PCNA were recruited within HSV-1-induced AAV RCs. Polymerase ␦ was not identified but subsequently was shown to colocalize with Rep within AAV RCs even in the presence of the HSV-1 polymerase complex. In addition, we found that AAV replication is associated with the recruitment of components of the Mre11/Rad50/Nbs1 complex, Ku70 and -86, and the mismatch repair proteins MSH2, -3, and -6. Finally, several HSV-1 factors were also found to be associated with Rep, including UL12. We demonstrated for the first time that this protein plays a role during AAV replication by enhancing the resolution of AAV replicative forms and AAV particle production. Altogether, these analyses provide the basis to understand how AAV adapts its replication strategy to the nuclear environment induced by the helper virus.

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“…UL12.5 localizes predominantly to mitochondria, where it triggers massive degradation of mitochondrial DNA early during HSV replication [132]. In addition to that UL12.5 has been found to acts directly within the mitochondrial matrix to degrade mitochondrial DNA by its nuclease activities [133].…”

Section: Use Of Molecular Mimicry By Viruses To Invade Mitochondriamentioning

confidence: 99%

Mitochondria as a Favourite Organelle for Invading Viruses

Reshi¹,

Hong²

2016

Mol Biol

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The self-destruction of cells infected with viruses undergoes the process of apoptosis generally to restrict infection and the spread of viral progeny. To avoid infection host has evolved interconnected complex defence network that comprises innate and acquired immune response. Mitochondria being considered as powerhouse of a cell is not limited to only energy production, but mitochondria perform various other functions in (disease, apoptosis and host innate immune system) which make them absolutely indispensable to the cell. This makes them a target of almost all the invading pathogens including viruses. Therefore being a multifunctional organelle, the viruses choose mitochondria as a favourite organelle as they can easily take control of the whole cell and make it to promote or block apoptosis as per their need.

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Epstein-Barr Virus Immediate-Early Protein Zta Co-Opts Mitochondrial Single-Stranded DNA Binding Protein To Promote Viral and Inhibit Mitochondrial DNA Replication

Cited by 47 publications

References 53 publications

Enhancement of Zta-activated lytic transcription of Epstein-Barr virus by Ku80

Enhancement of Zta-activated lytic transcription of Epstein-Barr virus by Ku80

Identification of Rep-Associated Factors in Herpes Simplex Virus Type 1-Induced Adeno-Associated Virus Type 2 Replication Compartments

Mitochondria as a Favourite Organelle for Invading Viruses

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