The DNA binding domains of the varicella-zoster virus gene 62 and herpes simplex virus type 1 ICP4 transactivator proteins heterodimerize and bind to DNA

Tyler, Jessica K.; Everett, Roger D.

doi:10.1093/nar/22.5.711

Cited by 18 publications

(14 citation statements)

References 58 publications

(63 reference statements)

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“…Two ocular-derived CD4 TCC recognize VZV peptide IE62 918-927 using discordant HLA-DR alleles and TCR Two protein domains of VZV IE62 and the orthologous HSV-1 protein ICP4 are highly conserved among alphaherpesvirinae: a domain that contains sites for DNA binding and homodimerization (IE62 463-636 and ICP4 ) and the large C-terminal region (IE62 750-1187 and ICP4 ) involved in transactivation of virus genes (28,40). Previously, we reported that IE62 is a common target Ag of the intraocular VZV-specific T cell response in VZV uveitis patients (18).…”

Section: Resultsmentioning

confidence: 99%

“…VZV IE62 and HSV ICP4 are abundantly expressed viral proteins that are transported from the nucleus to the cytoplasm for incorporation in the tegument of the virion during lytic infection (27,(60)(61)(62). Both viral proteins are large (∼1300 aa long) and contain a DNA binding and a large C-terminal transactivator domain that are both highly conserved among alphaherpesvirinae of diverse animal species (28,40,63). Previous studies showed that viral tegument proteins, including VZV IE62 and HSV-1 ICP4, are immunoprevalent targets of aHHV-specific CD4 and CD8 T cells in blood of healthy HSV-1-and/or VZV-infected adults (29,(64)(65)(66), lesions of genital herpes patients (67), affected eyes of herpetic uveitis and keratitis patients (18)(19)(20)68), and at the site of HSV-1 latency in human trigeminal ganglia (69).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Ouwendijk¹,

Geluk

Smits³

et al. 2014

The Journal of Immunology

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Intraocular varicella-zoster virus (VZV) and HSV type 1 (HSV-1) infections cause sight-threatening uveitis. The disease is characterized by an intraocular inflammatory response involving herpesvirus-specific T cells. T cell reactivity to the noncausative human alphaherpesvirus (αHHV) is commonly detected in the affected eyes of herpetic uveitis patients, suggesting the role of cross-reactive T cells in the disease. This study aimed to identify and functionally characterize intraocular human alphaherpesvirus cross-reactive T cells. VZV protein immediate early 62 (IE62), which shares extensive homology with HSV ICP4, is a previously identified T cell target in VZV uveitis. Two VZV-specific CD4 T cell clones (TCC), recovered from the eye of a VZV uveitis patient, recognized the same IE62918–927 peptide using different TCR and HLA-DR alleles. The IE62918–927 peptide bound with high affinity to multiple HLA-DR alleles and was recognized by blood-derived T cells of 5 of 17 HSV-1/VZV-seropositive healthy adults but not in cord blood donors (n = 5). Despite complete conservation of the IE62 epitope in the orthologous protein ICP4 of HSV-1 and HSV-2, the TCC recognized VZV and HSV-1– but not HSV-2–infected B cells. This was not attributed to proximal epitope-flanking amino acid polymorphisms in HSV-2 ICP4. Notably, VZV/HSV-1 cross-reactive CD4 T cells controlled VZV but not HSV-1 infection of human primary retinal pigment epithelium (RPE) cells. In conclusion, we report on the first VZV/HSV-1 cross-reactive CD4 T cell epitope, which is HLA-DR promiscuous and immunoprevalent in coinfected individuals. Moreover, ocular-derived peptide-specific CD4 TCC controlled VZV but not HSV-1 infection of RPE cells, suggesting that HSV-1 actively inhibits CD4 T cell activation by infected human RPE cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Ouwendijk¹,

Geluk

Smits³

et al. 2014

The Journal of Immunology

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“…Or, tout activateur transcriptionnel possède, en général, plusieurs domaines fonctionnels : un domaine de fixation à l'ADN, un domaine activateur et un signal de localisation nucléaire (figure 3). L'ensemble de la région 2 de l'IE62, et plus particulièrement les acides aminés 472 à 633, possède des propriétés de fixation à l'ADN et s'y fixe sous forme de dimères [19]. Une séquence, identifiée à l'intérieur du domaine de fixation à l'ADN pré-sente des similitudes frappantes avec l'hélice de l'homéodomaine reconnaissant l'ADN.…”

Section: Résidus Appelée Ie62 (175 Kda) Celle-ci Présente De Fortes unclassified

La régulation des cycles infectieux du virus de la varicelle et du zona.

Piette¹,

Maisieres²,

Baudoux-Tebache³

et al. 1998

Med Sci (Paris)

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“…The protein is 1,310 amino acids in length and contains a potent N-terminal acidic activation domain and a centrally located DNA binding domain. It is believed to be a native homodimer, based on comparison with its putative homolog HSV-1 ICP4 and the experimentally established dimerization of a bacterially expressed fragment containing the DNA-binding domain and sequences corresponding to the ICP4 dimerization domain (50).…”

mentioning

confidence: 99%

“…The IE62 DBD was also shown to interact with this sequence within the ICP4-binding sites present in the HSV ICP4 and gD promoters. Site-specific mutation of each nucleotide within the ICP4 consensus site showed that only mutations within the 5Ј ATCGT sequence affected IE62 DBD binding, whereas mutations in both the 5Ј and 3Ј sequences affected ICP4 binding (4,48,49,50). Tyler and Everett (49) showed that the DBD fragment interacted with several sequences within the ORF62 promoter, including three ATCGT consensus sites.…”

mentioning

confidence: 99%

Role of the IE62 Consensus Binding Site in Transactivation by the Varicella-Zoster Virus IE62 Protein

White

Hua

Hay

et al. 2010

J Virol

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The varicella-zoster virus (VZV) IE62 protein is the major transcriptional activator. IE62 is capable of associating with DNA both nonspecifically and in a sequence-specific manner via a consensus binding site (5-ATCGT-3). However, the function of the consensus site is poorly understood, since IE62 efficiently transactivates promoter elements lacking this sequence. In the work presented here, sequence analysis of the VZV genome revealed the presence of 245 IE62 consensus sites throughout the genome. Some 54 sites were found to be present within putative VZV promoters. Electrophoretic mobility shift assay (EMSA) experiments using an IE62 fragment containing the IE62 DNA-binding domain and duplex oligonucleotides that did or did not contain the IE62 consensus binding sequence yielded K D (equilibrium dissociation constant) values in the nanomolar range. Further, the IE62 DNA binding domain was shown to have a 5-fold-increased affinity for its consensus site compared to nonconsensus sequences. The effect of consensus site presence and position on IE62-mediated activation of native VZV and model promoters was examined using site-specific mutagenesis and transfection and superinfection reporter assays. In all promoters examined, the consensus sequence functioned as a distance-dependent repressive element. Protein recruitment assays utilizing the VZV gI promoter indicated that the presence of the consensus site increased the recruitment of IE62 but not Sp1. These data suggest a model where the IE62 consensus site functions to down-modulate IE62 activation, and interaction of IE62 with this sequence may result in loss or decrease of the ability of IE62 to recruit cellular factors needed for full promoter activation.Varicella-zoster virus (VZV) is a human alphaherpesvirus that causes varicella (chicken pox) and establishes latency in cells within dorsal root ganglia during primary infection. Upon reactivation, VZV causes shingles, or zoster, which usually involves productive infection along a single dermatome and infection of the skin innervated by that dermatome (1). Productive VZV infection during either primary infection or reactivation results in the expression of the entire coding capacity of the 125-kb VZV genome, leading to the synthesis of some 70 proteins. The immediate-early 62 (IE62) protein, the major viral transcriptional activator, is capable of transactivating the majority of if not all VZV promoters during lytic infection. It is also capable of transactivating heterologous promoters and model promoters containing a minimal number of cis-acting elements. IE62 is required for viral growth in tissue culture and increases the infectivity of VZV DNA (32, 42). The protein is 1,310 amino acids in length and contains a potent N-terminal acidic activation domain and a centrally located DNA binding domain. It is believed to be a native homodimer, based on comparison with its putative homolog HSV-1 ICP4 and the experimentally established dimerization of a bacterially expressed fragment containing the DNA-binding do...

show abstract

The DNA binding domains of the varicella-zoster virus gene 62 and herpes simplex virus type 1 ICP4 transactivator proteins heterodimerize and bind to DNA

Cited by 18 publications

References 58 publications

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

La régulation des cycles infectieux du virus de la varicelle et du zona.

Role of the IE62 Consensus Binding Site in Transactivation by the Varicella-Zoster Virus IE62 Protein

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