Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus

Benz, Christine; Reusch, Uwe; Muranyi, Walter; Brune, Wolfram; Atalay, Ramazan; Hengel, Hartmut

doi:10.1099/0022-1317-82-9-2061

Cited by 15 publications

(10 citation statements)

References 56 publications

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“…4) implies dose responsiveness similar to down-regulation of MHC class I surface expression by other herpesviruses (25)(26)(27)(28). Overall, our results are consistent with reports that NPC cells and cultured NPC cell lines display class I cell surface HLA (45,46) but indicate that they do so at reduced levels.…”

Section: Discussionsupporting

confidence: 82%

“…The inverse correlation of EBNA1 and HLA mRNA levels seemed similar to recently reported dose-responsive effects of two other herpesviruses on MHC class I HLA expression: HCMV and KSHV inhibited HLA expression by 2-to 3-fold and 2-to 5-fold, respectively (25)(26)(27)(28). Similarly, in our study, quantitative real-time PCR showed that, compared with normal epithelium, the 10 highest EBNA1 NPC tumors had an average of 4.5-fold decreased HLA mRNA levels, whereas in the 10 lowest EBNA1 tumors HLA mRNA levels were decreased on average 2.1-fold (Supplementary Table S6).…”

Section: Resultssupporting

confidence: 59%

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Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma

Sengupta

Boon

Chen³

et al. 2006

Cancer Research

202

192

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To identify the molecular mechanisms by which EBVassociated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogenemediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC. (Cancer Res 2006; 66(16): 7999-8006)

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Section: Discussionsupporting

confidence: 82%

Section: Resultssupporting

confidence: 59%

Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma

Sengupta

Boon

Chen³

et al. 2006

Cancer Research

202

192

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“…The CMV inhibition of immunoproteasome formation restricts the diversity of epitopes presented in productively infected nonhematopoietic stromal and parenchymal tissue. Additionally, in these cell types, the MHC class I function is most efficiently downregulated by a multitude of CMV inhibitors (7). Taking these data together, it is tempting to speculate that CMV misleads the CD8 ϩ -T-cell response when primed by peptides derived from infected or cross-presenting professional APC that are not generated by CMV-infected nonhematopoietic cells lacking immunoproteasomes.…”

Section: Discussionmentioning

confidence: 99%

A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Khan

Zimmermann

Basler

et al. 2004

J Virol

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Both human and mouse cytomegaloviruses (HCMV and MCMV) avoid peptide presentation through the major histocompatibility complex (MHC) class I pathway to CD8؉ T cells. Within the MHC class I pathway, the vast majority of antigenic peptides are generated by the proteasome system, a multicatalytic protease complex consisting of constitutive subunits, three of which can be replaced by enzymatically active gamma interferon (IFN-␥)-inducible subunits, i.e., LMP2, LMP7, and MECL1, to form the so-called immunoproteasomes. Here, we show that steady-state levels of immunoproteasomes are readily formed in response to MCMV infection in the liver. In contrast, the incorporation of immunoproteasome subunits was prevented in MCMVinfected, as well as HCMV-infected, fibroblasts in vitro. Likewise, the expression of the IFN-␥-inducible proteasome regulator PA28␣␤ was also impaired in MCMV-infected cells. Both MCMV and HCMV did not alter the constitutive-subunit composition of proteasomes in infected cells. Quantitative assessment of LMP2, MECL1, and LMP7 transcripts revealed that the inhibition of immunoproteasome formation occurred at a pretranscriptional level. Remarkably, a targeted deletion of the MCMV gene M27, encoding an inhibitor of STAT2 that disrupts IFN-␥ receptor signaling, largely restored transcription and protein expression of immunoproteasome subunits in infected cells. While CMV block peptide transport and MHC class I assembly by posttranslational strategies, immunoproteasome assembly, and thus the repertoire of proteasomal peptides, is controlled by pretranscriptional mechanisms. We hypothesize that the blockade of immunoproteasome formation has considerable consequences for shaping the CD8 ؉ -T-cell repertoire during the effector phase of the immune response.Human cytomegalovirus (HCMV), a prototype member of the betaherpesvirus subfamily, is an important pathogen and can cause a wide range of disease manifestations. Primary infection in the immunocompetent host is usually asymptomatic, whereas in the immunocompromised host infection or virus reactivation from latency can cause severe and even fatal disease. Mouse cytomegalovirus (MCMV) shows a similar pathobiology and has a collinear genome (47). Studies of humans and of the mouse have revealed that virus-specific CD8 ϩ T lymphocytes represent the dominant effector arm of protective immunity. For immune recognition, the infected cells present virus-derived peptides on their major histocompatibility complex (MHC) class I molecules to CD8 ϩ cytotoxic T lymphocytes. The processing and presentation of viral peptides is therefore the basis for immune recognition of infected cells, and a change in or lack of peptide supply can undermine the efficiency of T-cell recognition and result in immune evasion of the virus. Both HCMV and MCMV avoid peptide presentation by the expression of several viral glycoproteins (gps) controlling distinct checkpoints of the MHC class I presentation pathway. Specifically, the HCMV US6-encoded gp shuts off the translocation of peptides acr...

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“…STAT2 has been reported to interact physically with the HCMV IE1/pp72 protein (Paulus et al, 2006), raising the possibility that STAT2 degradation contributes to the regulation of IE1/ pp72 either by degradation of the IE1/pp72-STAT2 complex or by concomitant degradation of IE1/pp72. In fact, pp72 is the subject of active regulation by HCMV (Grey et al, 2007) and the relative abundance of pp72 decreases with the progress of HCMV replication (Benz et al, 2001;White & Spector, 2005). Another explanation could be that STAT2 is an independent target of immune evasion due to its STAT1-independent functions.…”

Section: Potential Consequences Of Stat2 Degradationmentioning

confidence: 99%

Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation

Trilling

Wilborn

et al. 2008

Journal of General Virology

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We have investigated the role of signal transducer and activator of transcription (STAT) 2 during human cytomegalovirus (HCMV) replication and found that protein levels of STAT2 are downregulated. STAT2 downregulation was observed in HCMV clinical isolates and laboratory strains with the exception of strain Towne. The HCMV-induced loss of STAT2 protein occurred despite an increased accumulation of STAT2 mRNA; it required HCMV early gene expression. The decrease in STAT2 was sensitive to proteasome inhibition, suggesting degradation of STAT2 via the ubiquitin proteasome pathway. Notably, pUL27, the HCMV homologue of the mouse CMV pM27 protein, which mediates the selective proteolysis of STAT2, did not induce STAT2 downregulation. Moreover, preceding STAT2 degradation, alpha/beta interferon (IFN)-receptormediated tyrosine phosphorylation of STAT2 was inhibited in HCMV-infected cells. This effect was paralleled by impaired tyrosine activation of STAT1 and STAT3. Accordingly, IFNs affected the replication efficiency of STAT2 degrading and non-degrading HCMV strains to a similar degree. In summary, HCMV abrogates IFN receptor signalling at multiple checkpoints by independent mechanisms including UL27-independent degradation of STAT2 and a preceding blockade of STAT2 phosphorylation. INTRODUCTIONCytomegaloviruses (CMVs) are members of the betaherpesvirus sub-family which persist for life in infected hosts through consecutive phases of productive and latent infection. While infection of immunocompetent individuals is usually subclinical, human cytomegalovirus (HCMV) can cause severe disease in transplant patients, people with primary or acquired immundeficiency or newborns after congenital infection (Mocarski et al., 2007). Immune control of mouse CMV (MCMV) infection is organized in a hierarchical and redundant manner by distinct components of innate and adaptive immunity (Polic et al., 1998). Interferons (IFNs) provide a direct defence against CMVs and connect innate and adaptive immunity (Lucin et al., 1992;Heise et al., 1998;Polic et al., 1998). Binding of IFN-a/b and IFN-c to their cognate transmembrane receptors initiates distinct Jak-signal transducer and activator of transcription (Jak-STAT)-dependent signalling pathways (Darnell, 1997;Stark et al., 1998). IFN receptors are composed of two subunits. Upon ligand binding, receptor-associated Jak kinases are activated and phosphorylate STAT proteins which subsequently dimerize, translocate to the nucleus and induce IFNdependent gene expression. Experimental studies using MCMV indicate that IFN receptor-induced Jak-STAT signalling has an indispensable role in the control of CMV replication by the host immune system (Lucin et al., 1992(Lucin et al., , 1994Heise et al., 1998;Presti et al., 1998). By replicating under the selective pressure of IFNs, CMVs have evolved effective mechanisms that counteract IFN induction (Le et al., 2008) and IFN-mediated antiviral defence mechanisms Zimmermann & Hengel, 2006).CMVs are able to interfere with IFN-dependent signal transdu...

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Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus

Abstract: Liver and intestinal epithelial cells are a major target of infection by cytomegaloviruses (CMV),

Cited by 15 publications

References 56 publications

Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma

Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma

A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation

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