The regions important for the activator and repressor functions of herpes simplex virus type 1 alpha protein ICP27 map to the C-terminal half of the molecule

Hardwicke, Mary Ann; Vaughan, Patrick; Sekulovich, Rose E.; O'Conner, R; Sandri-Goldin, R. M.

doi:10.1128/jvi.63.11.4590-4602.1989

Cited by 78 publications

(120 citation statements)

References 94 publications

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“…Expression of the IE63 protein was required for this virally mediated effect on 3Ј processing, and this is in accordance with previous data which demonstrated, with a range of virus mutants deficient in IE gene expression and by transient transfection studies, that this on July 10, 2020 by guest http://jvi.asm.org/ gene product was essential for upregulation of poly(A) site usage (28). Several studies have demonstrated that the IE63 protein is involved in the regulation of HSV gene expression (11,30,39,43,44) and is specifically required for late gene expression (13,39). The plethora of conflicting information and the apparently multifunctional nature of the IE63 protein have, however, made identification of the specific mechanism(s) of this regulation difficult.…”

Section: Discussionsupporting

confidence: 91%

“…The 63-kDa IE protein (IE63 or ICP27) encoded by the UL54 gene (26) is a nuclear phosphoprotein and is one of two IE proteins essential for lytic virus replication. IE63 plays a key role in the switch from early to late gene expression (37,39), and this multifunctional protein has both trans-repressor and trans-activator functions (11,30,43,44). Transfection studies have demonstrated that IE63 acts synergistically with IE pro-teins IE175 and IE110 to repress expression from IE and early promoters and activate expression from late promoters (11,30,43); IE63 also affects the cellular localization of these two IE proteins (41,44).…”

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confidence: 99%

“…IE63 plays a key role in the switch from early to late gene expression (37,39), and this multifunctional protein has both trans-repressor and trans-activator functions (11,30,43,44). Transfection studies have demonstrated that IE63 acts synergistically with IE pro-teins IE175 and IE110 to repress expression from IE and early promoters and activate expression from late promoters (11,30,43); IE63 also affects the cellular localization of these two IE proteins (41,44). At the posttranscriptional level of gene regulation, enhancement of gene expression correlates with the ability of IE63 to stimulate 3Ј processing (28,29,42) at certain poly(A) sites whereas the repressor function is associated with an inhibition of splicing.…”

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confidence: 99%

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Regulation of herpes simplex virus poly (A) site usage and the action of immediate-early protein IE63 in the early-late switch

McGregor

Phelan

Dunlop

et al. 1996

J Virol

102

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The essential herpes simplex virus type 1 (HSV-1) immediate-early protein IE63 (ICP27) is pleiotropic in function, promoting the switch from the early to late phase of virus gene expression, and has effects on the posttranscriptional processes of mRNA splicing and 3 processing. We have investigated the role of IE63 in the regulation of viral mRNA 3 processing and of late gene expression. Our in vitro 3 processing studies demonstrated that HSV-1 infection induces an activity, which requires IE63 gene expression, responsible for an observed increase in 3 processing of selected HSV-1 poly(A) sites. Processing efficiencies at the poly(A) sites of two late genes, UL38 and UL44, shown to be inherently weak processing sites, were increased by the IE63-induced activity. In contrast, 3 processing at the poly(A) sites of selected immediate-early and early genes, stronger processing sites, was unaffected by IE63 expression. UV cross-linking experiments demonstrated that HSV infection caused enhanced binding of protein factors, including the 64-kDa component of cleavage stimulation factor (CstF), to poly(A) site RNAs from virus genes of all temporal classes and that this enhanced binding required expression of IE63. By immunofluorescence, the homogeneous pattern of the 64-kDa CstF protein distribution became slightly clumped with infection, whereas the splicing small nuclear ribonucleoprotein particles were reorganized into a highly punctate distribution away from the sites of virus transcription. This effect could create an increase in the relative concentration of 3 processing factors available to pre-mRNAs. Western blot (immunoblot) analysis showed that IE63 was required for expression of several true late genes and for the efficient and timely expression of the UL29 and UL42 early genes, integral components of the viral DNA synthesis machinery. Our data are consistent with two effects of IE63 on late gene regulation: firstly, a stimulation of pre-mRNA 3 processing and, secondly, as a requirement for expression of functions necessary for viral DNA synthesis.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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confidence: 99%

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Regulation of herpes simplex virus poly (A) site usage and the action of immediate-early protein IE63 in the early-late switch

McGregor

Phelan

Dunlop

et al. 1996

J Virol

102

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“…Our general approach was mutational dissection of the pro region of the TGFOI precursor to investigate the structural features that are important in posttranslational events such as proteolytic processing, disulfide bridge formation, protein secretion and latent complex formation . Linker insertional mutagenesis has been successfully used to study functional domains within the v-fps (Stone et al ., 1984), glucocorticoid receptor (Giguere et al, 1986), c-myc (Stone et al ., 1987), v-fms (Lyman et al, 1987), and HSV 1 (Hardwicke et al ., 1989) . This type of mutagenesis provides evenly distributed in-frame insertion of several amino acids throughout the protein coding region by introducing synthetic oligonucleotide linkers at specific restriction sites.…”

Section: Construction Of a Series Of Inframe Insertion And Deletion Mmentioning

confidence: 99%

Identification and analysis of discrete functional domains in the pro region of pre-pro-transforming growth factor beta 1.

Sha

Gentry

1991

The Journal of Cell Biology

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Abstract. A series of site-specific insertion and deletion mutants was prepared in the pro domain of transforming growth factor ,Q1 (TGFa1) encoded by simian TGF01 cDNA. These mutants were transiently ex pressed in COS-1 cells and the ability of each to be properly processed, folded correctly, and secreted was determined by immunoblot analysis of cells and culture supernatants . Insertions in regions corresponding to amino acid residues 50, 154, and 170 blocked secretion ; culture supernatants from COS-1 cells showed no immunologically reactive proteins, whereas intact cells contained high levels of the mutant polypeptides. Insertions in the middle portion of the pro domain at residues 81, 85, and 144 affected disulfide maturation of the mature TGFOL An insertion at residue 110, on T RANSFORMING growth factor-beta-I (TGF#I)' is a potent regulator of cell growth and differentiation Sporn, 1988, 1990;Barnard et al., 1990) . Following the initial purification and characterization of TGFQI as a homodimeric, 24-kD polypeptide (Assoian et al., 1983;Frolik et al ., 1983 ;Roberts et al ., 1983), several distinct but related TGF# family members have been cloned and analyzed by cDNA sequencing (Derynck et al ., 1985(Derynck et al ., , 1988 deMartin et al ., 1987; ten-Dijke et al ., 1988;Hanks et al ., 1988; Jakowlew et al ., 1988a,b ;Madisen et al ., 1988), indicating that they share similar structural properties. These novel TGFos are encoded as large precursors and each is processed from the carboxyl-terminus of its precursor by proteolytic cleavage . The mature TGFas all show considerable sequence similarity (-80%) and contain nine cysteine residues which can be perfectly aligned in sequence. The pro domains ofeach precursor contain three aligned cysteine residues as well as several sites for N-linked glycosylation. Since the pro portions of each precursor show less sequence similarity (<50%), each form of the growth factor may be secreted and activated differently.Studies on posttranslational modification and processing of the TGF01 precursor have been derived from sequence 1. Abbreviations used in this paper: LAP, latency-associated peptide ; TGF01, transforming growth factor 01 .

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“…Most attention on the 512-amino-acid IE63 protein in recent years has focused on its potential role in 3Ј mRNA and poly(A) processing, splicing, and mRNA stabilization events (43,47,58,72). Mutations involved in both the positive and negative modulatory effects of IE63 have been mapped to the Cys-rich C terminus (26,42,64), which contains one of only three small minimally conserved motifs. Recently, an unusual activator domain requiring specific conserved Cys and His residues has been mapped to this location by GAL4 fusion experiments in the varicella-zoster virus homolog (55).…”

mentioning

confidence: 99%

Evaluation of colocalization interactions between the IE110, IE175, and IE63 transactivator proteins of herpes simplex virus within subcellular punctate structures

Mullen

Gerstberger

Ciufo

et al. 1995

J Virol

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A number of previous studies have implied that three herpes simplex virus-encoded nuclear transactivator proteins, IE175 (ICP4), IE110 (ICP0), and IE63 (ICP27), may cooperate in transcriptional and posttranscriptional stimulation of viral gene expression. Using double-label immunofluorescence assays (IFA) in transient expression assays, we have examined the intracellular localization of these three proteins in DNA-transfected cells. The IE110 protein on its own forms spherical punctate domains within the nucleus, whereas the IE175 and IE63 proteins alone give uniform and speckled diffuse patterns, respectively. In infected cells, the IE110 punctate granules have been shown to correspond to novel preexisting subnuclear structures referred to as ND10 domains or PODs that contain a variety of cellular proteins, including SP100 and the PML proto-oncogene product. Cotransfection experiments with wild-type nuclear forms of both IE175 and IE110 provided direct evidence for partial redistribution of IE175 into the same punctate granules that contained IE110. Surprisingly, nuclear forms of IE110 were found to move a cytoplasmic form of IE175 into nuclear punctate structures, and a cytoplasmic form of IE110 was able to retain nuclear forms of IE175 in cytoplasmic punctate structures. Therefore, the punctate characteristic of IE110 appeared to both dominate the interactions and override the normal nuclear localization signals. The domains responsible for the interaction mapped to between codons 518 and 768 in IE110 and to between codons 835 and 1029 in IE175. Importantly, a truncated nuclear form of the 1,298-amino-acid IE175 protein, which lacked the C-terminal domain beyond codon 834, was found to be excluded from the IE110 punctate granules. Cotransfection of nuclear or cytoplasmic IE110 with a truncated nuclear form of IE63 also led to partial redistribution of IE63 into either nuclear or cytoplasmic punctate granules containing IE110. Both the IE63-IE110 and IE175-IE110 colocalization interactions were demonstrated in Vero cells but not in 293 cells. Consequently, they differ from IE110 self-interactions, which correlate with in vitro dimerization and occur efficiently in both cell types. These interactions may help to explain the altered promoter target specificity and synergism observed when IE175 is cotransfected with IE110 in transactivation studies.

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The regions important for the activator and repressor functions of herpes simplex virus type 1 alpha protein ICP27 map to the C-terminal half of the molecule

Cited by 78 publications

References 94 publications

Regulation of herpes simplex virus poly (A) site usage and the action of immediate-early protein IE63 in the early-late switch

Regulation of herpes simplex virus poly (A) site usage and the action of immediate-early protein IE63 in the early-late switch

Identification and analysis of discrete functional domains in the pro region of pre-pro-transforming growth factor beta 1.

Evaluation of colocalization interactions between the IE110, IE175, and IE63 transactivator proteins of herpes simplex virus within subcellular punctate structures

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