An enhancer element in the short unique region of human cytomegalovirus regulates the production of a group of abundant immediate early transcripts

Weston, Kathleen

doi:10.1016/0042-6822(88)90481-3

Cited by 110 publications

(133 citation statements)

References 33 publications

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“…A 260 bp BamH1 -Xho1 fragment of the human IgH intronic enhancer, containing three mE motifs (mE1, mE2, mE4) and the mA, mC, mB, and OCTA motifs, was inserted down-stream of the SV40 promoter of the pGL2 promoter vector (Pedersen, unpublished). To assess activity of the rat IgH hs1,2 3'enhancer, we used the constructs pbG128-3'E (Grant et al, 1992), pbG128 and pbG128-SV40 (Weston, 1988) and RNase protection mapping protocol as described in Andersen et al (1997). The reporter plasmids pKappaLucE (wild-type murine k promoter) and pKappa0 -LucE (mutated octamer site) are described in Strubin et al (1995).…”

Section: Transfection and Reporter Gene Assaysmentioning

confidence: 99%

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

et al. 2002

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In classical Hodgkin lymphoma the malignant Hodgkin/ Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3' enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cellspecific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1 and PAX-5 are significantly down-regulated in HRS cells in pathological specimens from primary tumour tissues. However, forced expression of these transcription factors can activate regulatory sequences of silenced B cell marker genes, and in one instance also transcription from a silenced endogenous locus. Thus, HRS cells are dedifferentiated B cells with global down-regulation of B cell-specific genes.

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Section: Transfection and Reporter Gene Assaysmentioning

confidence: 99%

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

et al. 2002

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“…This indicated that one or more functions encoded in the US2-11 region suppressed MHC I presentation efficiently under IE conditions. The most likely candidate to mediate this effect was US3, which had been identified as an IE gene (Greijer et al, 2001;Liu et al, 2002;Weston, 1988). A 22 kDa isoform of gpUS3, encoded by an unspliced transcript, causes MHC I retention in the ER (Ahn et al, 1996;Jones et al, 1996;Lee et al, 2000;Park et al, 2004), whereas a 17 kDa isoform, encoded by a singly spliced transcript, has a dominant-negative effect when expressed together with the full-length protein (Liu et al, 2009;Shin et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…These results showed that US2-11 genes were indeed interfering with functional antigen presentation under IE conditions. US3 expression is insufficient to suppress MHC I presentation in the IE phase of infection gpUS3 is the only member of the US2-11-encoded immunoevasion proteins that had been reported to be expressed at IE times (Greijer et al, 2001;Liu et al, 2002;Weston, 1988). We therefore investigated whether the reduction of IE1 peptide presentation at IE times was mediated by gpUS3.…”

Section: Deletion Of Us2-11 Restores Presentation Of Ie1 Peptides By mentioning

confidence: 99%

“…This is consistent with the idea that expression kinetics of gpUS2, gpUS3, gpUS6 and gpUS11 overlap considerably at early and late phases of HCMV infection, thereby guaranteeing an optimal protection of infected cells against CTL recognition. In contrast, gpUS3 was reported to be the only evasion protein expressed at immediate-early (IE) times of infection (Ahn et al, 1996;Weston, 1988). This is a critical phase in the lytic cycle of the virus, as both exogenously introduced structural proteins and regulatory IE proteins are present in abundance at this time postinfection (p.i.).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection

Hesse

Ameres

Besold

et al. 2013

Journal of General Virology

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Human cytomegalovirus (HCMV) interferes with MHC class I-restricted antigen presentation and thereby reduces recognition by CD8 + T-cells. This interference is mediated primarily by endoplasmic reticulum-resident glycoproteins that are encoded in the US2-11 region of the viral genome. Such a suppression of recognition would be of particular importance immediately after infection, because several immunodominant viral antigens are already present in the cell in this phase. However, which of the evasion proteins gpUS2-11 interfere(s) with antigen presentation to CD8 + T-cells at this time of infection is not known. Here we address this question, using recombinant viruses (RV) that express only one of the immunoevasins gpUS2, gpUS3 or gpUS11. Infection with RV-US3 had only a limited impact on the presentation of peptides from the CD8 + T-cell antigens IE1 and pp65 under immediate-early (IE) conditions imposed by cycloheximide/ actinomycin D blocking. Unexpectedly, both RV-US2 and RV-US11 considerably impaired the recognition of IE1 and pp65 by CD8 + T-cells, and both US2 and, to a lesser extent, US11 were transcribed under IE conditions. Thus, gpUS2 and gpUS11 are key effectors of MHC class I immunoevasion immediately after HCMV infection.

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“…and substantially reduced thereafter, expression of US10 and US11, of US8 and US9, and of US6 and US7 peaks at 8, 24 and 48 h p.i., respectively (Jones et al, 1991;Tenney & Colberg-Poley, 1991;Weston, 1988). To assess whether addition of hygro at different times p.i.…”

Section: Presence Of the Us2-us11 Genomic Region Confers Protection Fmentioning

confidence: 99%

Human cytomegalovirus US9 protein contains an N-terminal signal sequence and a C-terminal mitochondrial localization domain, and does not alter cellular sensitivity to apoptosis

Mandic

Miller

Coulter

et al. 2009

Journal of General Virology

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The human cytomegalovirus (CMV) US2-US11 genomic region contains a cluster of genes whose products interfere with antigen presentation by the major histocompatibility complex (MHC) proteins. Although included in this cluster, the US9 gene encodes a glycoprotein that does not affect MHC activity and whose function is still largely uncharacterized. An in silico analysis of the US9 amino-acid sequence uncovered the presence of an N-terminal signal sequence (SS) and a C-terminal transmembrane domain containing the specific hallmarks of known mitochondrial localization sequences (MLS). Expression of full-length US9 and of US9 deletion mutants fused to GFP revealed that the N-terminal SS mediates US9 targeting to the endoplasmic reticulum (ER) and that the C-terminal MLS is both necessary and sufficient to direct US9 to mitochondria in the absence of a functional SS. This dual localization suggested a possible role for US9 in protection from apoptosis triggered by ER-to-mitochondria signalling. Fibroblasts infected with the US2-US11 deletion mutant virus RV798 or with the parental strain AD169varATCC were equally susceptible to death triggered by exposure to tumour necrosis factor (TNF)-a, tunicamycin, thapsigargin, brefeldin A, lonidamine and carbonyl cyanide m-chloro phenyl hydrazone, but were 1.6-fold more sensitive to apoptosis induced by hygromycin B. Expression of US9 in human embryonic kidney 293T cells or in fibroblasts, however, did not protect cells from hygromycin B-mediated death. Together, these results classify US9 as the first CMV-encoded protein to contain an N-terminal SS and a C-terminal MLS, and suggest a completely novel role for this protein during infection. INTRODUCTIONHuman cytomegalovirus (CMV) is a very prevalent betaherpesvirus that poses serious medical concerns in immunocompromised individuals . The ability to evade or modulate host immune responses, coupled with the capacity to establish latency after primary infection, is at the basis of the tremendous success of CMV as a human pathogen.The US2-US11 genomic region has been shown to be dispensable for viral replication in primary human fibroblasts (HF) (Jones & Muzithras, 1992;Kollert-Jons et al., 1991), and to encode five endoplasmic reticulum (ER)-resident glycoproteins, US2, US3, US6, US10 and US11, that disrupt antigen presentation by the major histocompatibility complex (MHC) class I and class II proteins (Lin et al., 2007). Despite sharing some very limited homology with US6, US10 and US11, US9 does not bind to or reduce MHC cell surface levels (Hegde et al., 2002(Hegde et al., , 2006Pereira et al., 1995). US9 was originally described as a member of the US6 family of proteins, which includes the products of the US6-US11 genes. These proteins contain markedly hydrophobic sequences at both the N-and C-termini, and were predicted to insert into cellular membranes (Weston & Barrell, 1986). US9 intracellular localization was initially examined in nonpolarized Madin-Darby canine kidney cells constitutively expressing a C-terminal-tagged ...

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An enhancer element in the short unique region of human cytomegalovirus regulates the production of a group of abundant immediate early transcripts

Cited by 110 publications

References 33 publications

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection

Human cytomegalovirus US9 protein contains an N-terminal signal sequence and a C-terminal mitochondrial localization domain, and does not alter cellular sensitivity to apoptosis

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