HCMV pUL135 Remodels the Actin Cytoskeleton to Impair Immune Recognition of Infected Cells

Stanton, Richard J.; Prod’homme, Virginie; Purbhoo, Marco A.; Moore, Melanie; Aicheler, Rebecca; Heinzmann, Marcus; Bailer, Susanne M.; Haas, Jürgen; Antrobus, Robin; Weekes, Michael P.; Lehner, Paul J.; Vojtěšek, Bořivoj; Miners, Kelly L.; Man, Stephen; Wilkie, Gavin S.; Davison, Andrew J.; Wang, Edward Chung Yern; Tomašec, Peter; Wilkinson, Gavin William Grahame

doi:10.1016/j.chom.2014.07.005

Cited by 71 publications

(76 citation statements)

References 42 publications

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“…Along these lines, it is intriguing to consider how UL135 may alter exosome composition in HCMV-infected ECs and to speculate on the potential impact of this manipulation on virus dissemination and inflammation of the endothelium. It was reported recently that pUL135 remodels the actin cytoskeleton through an interaction with ABI1 and ABI2 to evade natural killer cell recognition (56), and these interactions have also been observed in our laboratory (M. Rak and F. Goodrum, unpublished results). These host interactions might underlie pUL135-mediated remodeling of the cytoskeleton for proper formation of the VAC, incorporation of virus particles into MVB, and virus maturation in ECs.…”

Section: Discussionmentioning

confidence: 55%

“…We have previously analyzed the localization of pUL135 and pUL136 in fibroblasts (50,54). While all proteins encoded in the UL133/8 locus are associated with Golgi membranes and localize to the VAC at late times in infection, the protein encoded by UL135 exhibits cell surface localization early in infection (50) and associates with the cytoskeleton (56). UL136 is expressed as multiple protein isoforms, some of which localize with the Golgi apparatus while others are more diffusely distributed throughout the cytoplasm (54).…”

Section: Ul135mentioning

confidence: 99%

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Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Bughio

Umashankar

Wilson

et al. 2015

J Virol

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Endothelial cells (ECs) are a critical target of viruses, and infection of the endothelium represents a defining point in viral pathogenesis. Human cytomegalovirus (HCMV), the prototypical betaherpesvirus, encodes proteins specialized for entry into ECs and delivery of the genome to the nuclei of ECs. Virus strains competent to enter ECs replicate with differing efficiencies, suggesting that the virus encodes genes for postentry tropism in ECs. We previously reported a specific requirement for the UL133/8 locus of HCMV for replication in ECs. The UL133/8 locus harbors four genes: UL133, UL135, UL136, and UL138. In this study, we find that while UL133 and UL138 are dispensable for replication in ECs, both UL135 and UL136 are important. These genes are not required for virus entry or the expression of viral genes. The phenotypes associated with disruption of either gene reflect phenotypes observed for the UL133/8 NULL virus, which lacks the entire UL133/8 locus, but are largely distinct from one another. Viruses lacking UL135 fail to properly envelop capsids in the cytoplasm, produce fewer dense bodies (DB) than the wild-type (WT) virus, and are unable to incorporate viral products into multivesicular bodies (MVB). Viruses lacking UL136 also fail to properly envelop virions and produce larger dense bodies than the WT virus. Our results indicate roles for the UL135 and UL136 proteins in commandeering host membrane-trafficking pathways for virus maturation. UL135 and UL136 represent the first HCMV genes crucial for early-to late-stage tropism in ECs. H uman cytomegalovirus (HCMV) is a ubiquitous herpesvirus with 50 to 99% seroprevalence in the global population. Like all herpesviruses, HCMV persists for the lifetime of the host by way of latent infection (1-3). The persistence of HCMV is asymptomatic in immunocompetent individuals and is characterized by states of subclinical reactivation from latency and low-level virus shedding (1). However, in immunocompromised hosts, HCMV causes significant morbidity and mortality. Of particular concern are stem cell and solid-organ transplant patients, HIV/AIDS patients, and cancer patients undergoing chemotherapy or radiation regimens (4, 5). Additionally, HCMV is the leading cause of infectious disease-related birth defects in the United States, affecting 1 in 150 children born in the United States and most commonly resulting in mild to severe hearing loss (6). While CMV infection of seronegative women during pregnancy poses the most significant risk for severe sequelae in infants (microcephaly, cerebral palsy, and severe hearing loss or cognitive deficits), as many as 75% of congenital infections occur in infants whose mothers were seropositive at the time of conception, indicating that these infections result from reinfection or reactivation (7). Finally, the persistence of HCMV is increasingly associated with age-related pathologies, even when overt clinical symptoms are absent. Agerelated pathologies include vascular disease, immune dysfunction, and frailty (8-13)...

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Section: Discussionmentioning

confidence: 55%

Section: Ul135mentioning

confidence: 99%

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Bughio

Umashankar

Wilson

et al. 2015

J Virol

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“…The significance of the NK cell response against herpesviruses is also reflected by the various mechanisms that these pathogens have evolved to evade or delay it (4). Indeed, for beta-and gammaherpesviruses, a variety of molecular mechanisms avoiding the NK-mediated antiviral activity have been defined (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Remarkably and paradoxically, such mechanisms have remained largely elusive for the alphaherpesviruses (17).…”

mentioning

confidence: 99%

Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

Grauwet

Cantoni

Parodi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Herpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, allowing these pathogens to cause lifelong infections with periods of recurrent virus spread. Natural killer (NK) cells are central in the innate antiviral response. Here, we report that the gD glycoprotein of the alphaherpesviruses, pseudorabies virus and herpes simplex virus-2, displays previously uncharacterized immune evasion properties toward NK cells. Expression of the gD protein leads to degradation of CD112/nectin-2, a ligand for the NK-activating receptor DNAX accessory molecule 1 (DNAM-1). This impairs binding of DNAM-1 to the cell surface, thereby suppressing NK-mediated killing of virus-infected (or gD-transfected) cells. Identification of this previously unidentified immune evasion mechanism may contribute to the design of improved herpesvirus vaccines and herpesvirus-based therapeutic vectors.

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“…Notably, viruses deficient in UL133, UL138, or the soluble 23-/19-kDa isoforms of UL136 generate many infectious virus progeny in CD34 ϩ hematopoietic cells, whereas wild-type viruses generate few such progeny (11,12,15). Molecular studies have revealed that UL135 and UL136 promote cytoplasmic maturation of viral particles in endothelial cells (23,24), UL135 impairs immune synapse formation (26), and UL138 promotes cell surface expression of the tumor necrosis factor alpha (TNF-␣) receptor (TNFR) (27,28) as well as impairs cell surface expression of the multidrug resistance-associated protein-1 (MRP1) (18).…”

mentioning

confidence: 99%

Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency

Lee

Caviness

Albright

et al. 2016

J Virol

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The UL133-138 locus present in clinical strains of human cytomegalovirus (HCMV) encodes proteins required for latency and reactivation in CD34؉ hematopoietic progenitor cells and virion maturation in endothelial cells. The encoded proteins form multiple homo-and hetero-interactions and localize within secretory membranes. One of these genes, UL136 gene, is expressed as at least five different protein isoforms with overlapping and unique functions. Here we show that another gene from this locus, the UL138 gene, also generates more than one protein isoform. A long form of UL138 (pUL138-L) initiates translation from codon 1, possesses an amino-terminal signal sequence, and is a type one integral membrane protein. Here we identify a short protein isoform (pUL138-S) initiating from codon 16 that displays a subcellular localization similar to that of pUL138-L. Reporter, short-term transcription, and long-term virus production assays revealed that both pUL138-L and pUL138-S are able to suppress major immediate early (IE) gene transcription and the generation of infectious virions in cells in which HCMV latency is studied. The long form appears to be more potent at silencing IE transcription shortly after infection, while the short form seems more potent at restricting progeny virion production at later times, indicating that both isoforms of UL138 likely cooperate to promote HCMV latency. IMPORTANCELatency allows herpesviruses to persist for the lives of their hosts in the face of effective immune control measures for productively infected cells. Controlling latent reservoirs is an attractive antiviral approach complicated by knowledge deficits for how latently infected cells are established, maintained, and reactivated. This is especially true for betaherpesviruses. The functional consequences of HCMV UL138 protein expression during latency include repression of viral IE1 transcription and suppression of virus replication. Here we show that short and long isoforms of UL138 exist and can themselves support latency but may do so in temporally distinct manners. Understanding the complexity of gene expression and its impact on latency is important for considering potential antivirals targeting latent reservoirs. Human cytomegalovirus (HCMV) is a betaherpesvirus that causes birth defects and disease in immunocompromised and immunosuppressed patients and has been associated with cancers, cardiovascular disease, and immune dysfunction (1-3). HCMV productively (lytically) infects differentiated cells, such as fibroblasts, endothelial cells, and epithelial cells, and latently infects incompletely differentiated cells of the myeloid lineage, such as monocytes and CD34 ϩ hematopoietic progenitor cells (HPC) (4, 5). Productive infection in multiple cell types within the human host facilitates viral dissemination, while latency ensures lifelong persistence despite an effective immune response against lyticphase antigens. Periodic reactivations of latent infections into the productive phase perpetuate both lifelong infecti...

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HCMV pUL135 Remodels the Actin Cytoskeleton to Impair Immune Recognition of Infected Cells

Cited by 71 publications

References 42 publications

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency

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