The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance UL<i>b</i>′-Encoded Modulation of TNF-α Signaling

Le, Vu Thuy Khanh; Trilling, Mirko; Hengel, Hartmut

doi:10.1128/jvi.06005-11

Cited by 84 publications

(104 citation statements)

References 71 publications

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“…It is intriguing to speculate how these proteins may indirectly target one another through their interaction with cellular factors. While pUL138 has been shown to increase the levels of surface TNFR (31,32) and decrease the levels of surface MRP-1 (33), pUL135 has not been implicated in the counterregulation of these proteins. Our data suggest an elegant mechanism by which the virus coordinately regulates the expression of two determinants from a single genetic locus which oppose one another with respect to their effects on viral replication.…”

Section: Discussionmentioning

confidence: 99%

“…The pUL133-pUL138 complex appears to cooperatively function in promoting a latent infection, as viruses containing disruptions in pUL133, pUL138, or both replicate with increased efficiency in CD34 ϩ cells (27,30). pUL138 has been shown to increase cell surface levels of TNFR (31,32) and decrease surface levels of MRP-1 (33), although the significance of these surface alterations to viral infection is not completely understood. The roles of pUL135 and pUL136 have not yet been described.…”

mentioning

confidence: 99%

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Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection

Umashankar

Rak

Bughio

et al. 2014

J Virol

139

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The mechanisms by which viruses persist and particularly those by which viruses actively contribute to their own latency have been elusive. Here we report the existence of opposing functions encoded by genes within a polycistronic locus of the human cytomegalovirus (HCMV) genome that regulate cell type-dependent viral fates: replication and latency. The locus, referred to as the UL133-UL138 (UL133/8) locus, encodes four proteins, pUL133, pUL135, pUL136, and pUL138. As part of the ULb= region of the genome, the UL133/8 locus is lost upon serial passage of clinical strains of HCMV in cultured fibroblasts and is therefore considered dispensable for replication in this context. Strikingly, we could not reconstitute infection in permissive fibroblasts from bacterial artificial chromosome clones of the HCMV genome where UL135 alone was disrupted. The loss of UL135 resulted in complex phenotypes and could ultimately be overcome by infection at high multiplicities. The requirement for UL135 but not the entire locus led us to hypothesize that another gene in this locus suppressed virus replication in the absence of UL135. The defect associated with the loss of UL135 was largely rescued by the additional disruption of the UL138 latency determinant, indicating a requirement for UL135 for virus replication when UL138 is expressed. In the CD34 ؉ hematopoietic progenitor model of latency, viruses lacking only UL135 were defective for viral genome amplification and reactivation. Taken together, these data indicate that UL135 and UL138 comprise a molecular switch whereby UL135 is required to overcome UL138-mediated suppression of virus replication to balance states of latency and reactivation. IMPORTANCEMechanisms by which viruses persist in their host remain one of the most poorly understood phenomena in virology. Herpesviruses, including HCMV, persist in an incurable, latent state that has profound implications for immunocompromised individuals, including transplant patients. Further, the latent coexistence of HCMV may increase the risk of age-related pathologies, including vascular disease. The key to controlling or eradicating HCMV lies in understanding the molecular basis for latency. In this work, we describe the complex interplay between two viral proteins, pUL135 and pUL138, which antagonize one another in infection to promote viral replication or latency, respectively. We previously described the role of pUL138 in suppressing virus replication for latency. Here we demonstrate a role of pUL135 in overcoming pUL138-mediated suppression for viral reactivation. From this work, we propose that pUL135 and pUL138 constitute a molecular switch balancing states of latency and reactivation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection

Umashankar

Rak

Bughio

et al. 2014

J Virol

139

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“…Two of the UL/b' region gene products, UL144 and UL138, upregulate the TNFα-mediated NF-κB signaling (19,20). UL138, which is expressed during latent infection, modulates the cell surface expression of TNFR1, suggesting that TNF signaling may affect HCMV latency (20,21). UL144, which is expressed early in lytic infection, is a transmembrane glycoprotein with a short intracellular cytoplasmic tail.…”

Section: (2) Activation Mechanisms Observed In Clinical Strainsmentioning

confidence: 99%

Differential Regulation of NF-κB Signaling during Human Cytomegalovirus Infection

Kwon

Ahn

2015

J Bacteriol Virol

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NF-κB transcription factors are key regulators of immune and stress responses, apoptosis, and differentiation. Human cytomegalovirus (HCMV) activates or represses NF-κB signaling at different times during infection. An initial increase in NF-κB activity occurs within a few hours of infection. The virus appears to adapt to this change since initial viral gene expression is promoted by the elevated NF-κB activity. Because NF-κB upregulates innate immune responses and inflammation, it has also been suggested that HCMV needs to downregulate NF-κB signaling. Recent studies have shown that HCMV has various mechanisms that inhibit NF-κB signaling. HCMV reduces cell surface expression of tumor necrosis factor receptor 1 (TNFR1) and blocks the DNA binding activity of NF-κB. Furthermore, some HCMV tegument proteins antagonize NF-κB activation by targeting the key components of NF-κB signaling at late stages of infection. In this review, we summarize the recent findings on the relationship between HCMV and NF-κB signaling, focusing, in particular, on the viral mechanisms by which the NF-κB signaling pathway is inhibited.

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“…The latency-expressed UL138 ORF has recently been shown to modulate cell surface expression of TNF receptor 1 (26,27), suggesting that TNF signaling may impact HCMV latency, as has been shown for mouse CMV (36). A second connection between the TNF family and UL/b= region proteins is highlighted by the UL144 ORF, which shows high homology to the herpesvirus entry mediator (HVEM/TNFRSF14) (37,38).…”

mentioning

confidence: 93%

“…Several proteins encoded in this region have been established to perform immune-modulatory functions (26)(27)(28)(29)(30)(31)(32). Recently, this genomic locus has also been implicated in the regulation of experimental latency (18,33).…”

mentioning

confidence: 99%

The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

Poole

Walther

Raven

et al. 2013

J Virol

102

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It is generally accepted that, following primary infection, human cytomegalovirus (HCMV) establishes lifelong latency in CD34؉ progenitor cells and other derivative cells of the myeloid lineage. In this study, we show that the viral UL144 gene is expressed during latent infection in two cell types of the myeloid lineage, CD34؉ and CD14 ؉ monocytes, and that the UL144 protein is functional in latently infected monocytes. However, this latency-associated expression of UL144 occurs only in certain isolates of HCMV and depends on the presence of functional GATA-2 transcription factor binding sites in the UL144 promoter, in contrast to the viral latency-associated gene LUNA, which we also show is regulated by GATA-2 but expressed uniformly during latent infection independent of the virus isolate. Taken together, these data suggest that the HCMV latency-associated transcriptome may be virus isolate specific and dependent on the repertoire of transcription factor binding sites in the promoters of latencyassociated genes.

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The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α Signaling

Cited by 84 publications

References 71 publications

Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection

Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection

Differential Regulation of NF-κB Signaling during Human Cytomegalovirus Infection

The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

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