Viral Perturbations of Host Networks Reflect Disease Etiology

Gulbahce, Natali; Yan, Han; Dricot, Amélie; Padi, Megha; Byrdsong, Danielle; Franchi, Rachel; Lee, Deok-Sun; Rozenblatt-Rosen, Orit; Mar, Jessica C.; Calderwood, Michael A.; Baldwin, Amy; Zhao, Bo; Balaji, S.; Braun, Pascal; Simonis, Nicolas; Huh, Kyung-Won; Hellner, Karin; Grace, Miranda; Chen, Alyce A.; Rubio, Renee; Marto, Jarrod A.; Christakis, Nicholas A.; Kieff, Elliott; Roth, Frederick P.; Roecklein‐Canfield, Jennifer; DeCaprio, James A.; Cusick, Michael E.; Quackenbush, John; Hill, David E.; Münger, Karl; Vidal, Marc; Barabási, Albert‐László

doi:10.1371/journal.pcbi.1002531

Cited by 103 publications

(107 citation statements)

References 49 publications

(61 reference statements)

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“…A second promising example for the use of our broad data across disease categories is a comparison between genetic and infectious diseases. By analysing integrated data (virus targets, related PPIs and disease-gene associations) of the Epstein-Barr virus (EBV) and the human papillomavirus, a recent study 47 showed that these viruses perturb the host network in a highly localized fashion, indicating that primarily the proteins directly connected to viral targets play a mechanistic role in the implicated diseases. We examined the HSDN network for diseases with similar symptoms as EBV infections.…”

Section: Discussionmentioning

confidence: 99%

Human symptoms–disease network

Zhou¹,

Menche²,

Barabási³

et al. 2014

Nat Commun

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565

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In the post-genomic era, the elucidation of the relationship between the molecular origins of diseases and their resulting phenotypes is a crucial task for medical research. Here, we use a large-scale biomedical literature database to construct a symptom-based human disease network and investigate the connection between clinical manifestations of diseases and their underlying molecular interactions. We find that the symptom-based similarity of two diseases correlates strongly with the number of shared genetic associations and the extent to which their associated proteins interact. Moreover, the diversity of the clinical manifestations of a disease can be related to the connectivity patterns of the underlying protein interaction network. The comprehensive, high-quality map of disease-symptom relations can further be used as a resource helping to address important questions in the field of systems medicine, for example, the identification of unexpected associations between diseases, disease etiology research or drug design.

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Section: Discussionmentioning

confidence: 99%

Human symptoms–disease network

Zhou¹,

Menche²,

Barabási³

et al. 2014

Nat Commun

Self Cite

565

470

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“…Likewise, the HCMV UDG, UL114, was found to interact with the chromatin remodeling factor SMARCB1 and to participate in the recruitment of the chromatin remodeling complex onto replication foci (33). Although no BKRF3-interacting cellular proteins were identified in two previous yeast-two hybrid screening studies (68,69), it is still possible that BKRF3 also recruits the cellular machinery to support viral DNA replication.…”

Section: Discussionmentioning

confidence: 99%

Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

Liu

et al. 2014

J Virol

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Epstein-Barr virus (EBV) BKRF3 shares sequence homology with members of the uracil-N-glycosylase (UNG) protein family and has DNA glycosylase activity. Here, we explored how BKRF3 participates in the DNA replication complex and contributes to viral DNA replication. Exogenously expressed Flag-BKRF3 was distributed mostly in the cytoplasm, whereas BKRF3 was translocated into the nucleus and colocalized with the EBV DNA polymerase BALF5 in the replication compartment during EBV lytic replication. The expression level of BKRF3 increased gradually during viral replication, coupled with a decrease of cellular UNG2, suggesting BKRF3 enzyme activity compensates for UNG2 and ensures the fidelity of viral DNA replication. In immunoprecipitation-Western blotting, BKRF3 was coimmunoprecipitated with BALF5, the polymerase processivity factor BMRF1, and the immediate-early transactivator Rta. Coexpression of BMRF1 appeared to facilitate the nuclear targeting of BKRF3 in immunofluorescence staining. Residues 164 to 255 of BKRF3 were required for interaction with Rta and BALF5, whereas residues 81 to 166 of BKRF3 were critical for BMRF1 interaction in glutathione S-transferase (GST) pulldown experiments. Viral DNA replication was defective in cells harboring BKRF3 knockout EBV bacmids. In complementation assays, the catalytic mutant BKRF3(Q90L,D91N) restored viral DNA replication, whereas the leucine loop mutant BKRF3(H213L) only partially rescued viral DNA replication, coupled with a reduced ability to interact with the viral DNA polymerase and Rta. Our data suggest that BKRF3 plays a critical role in viral DNA synthesis predominantly through its interactions with viral proteins in the DNA replication compartment, while its enzymatic activity may be supplementary for uracil DNA glycosylase (UDG) function during virus replication. IMPORTANCECatalytic activities of both cellular UDG UNG2 and viral UDGs contribute to herpesviral DNA replication. To ensure that the enzyme activity executes at the right time and the right place in DNA replication forks, complex formation with other components in the DNA replication machinery provides an important regulation for UDG function. In this study, we provide the mechanism for EBV UDG BKRF3 nuclear targeting and the interacting domains of BKRF3 with viral DNA replication proteins. Through knockout and complementation approaches, we further demonstrate that in addition to UDG activity, the interaction of BKRF3 with viral proteins in the replication compartment is crucial for efficient viral DNA replication.

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“…A recent report defined the HIV proteome and noted that only 4% of the interactions defined in that mass spectrometry-based study had been previously reported in the VirusMINT database, highlighting the need for such global analyses (28). Other groups have reported the mapping of PPIs for HPV16 (21) or for E2 from several HPV types (45) by yeast two-hybrid analyses. The yeast two-hybrid approach may reveal new interactions but lacks the potential to address which proteins are expressed in the natural host cell type of HPV infection and cannot detect multiprotein complexes.…”

mentioning

confidence: 99%

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

White

Kramer

Tan

et al. 2012

J Virol

177

233

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We have begun to define the human papillomavirus (HPV)-associated proteome for a subset of the more than 120 HPV types that have been identified to date. Our approach uses a mass spectrometry-based platform for the systematic identification of interactions between human papillomavirus and host cellular proteins, and here we report a proteomic analysis of the E6 proteins from 16 different HPV types. The viruses included represent high-risk, low-risk, and non-cancer-associated types from genus alpha as well as viruses from four different species in genus beta. The E6 interaction data set consists of 153 cellular proteins, including several previously reported HPV E6 interactors such as p53, E6AP, MAML1, and p300/CBP and proteins containing PDZ domains. We report the genus-specific binding of E6s to either E6AP or MAML1, define the specific HPV E6s that bind to p300, and demonstrate several new features of interactions involving beta HPV E6s. In particular, we report that several beta HPV E6s bind to proteins containing PDZ domains and that at least two beta HPV E6s bind to p53. Finally, we report the newly discovered interaction of proteins of E6 of beta genus, species 2, with the Ccr4-Not complex, the first report of a viral protein binding to this complex. This data set represents a comprehensive survey of E6 binding partners that provides a resource for the HPV field and will allow continued studies on the diverse biology of the human papillomaviruses.T he human papillomaviruses (HPVs) comprise more than 120 different virus types, each with a double-stranded DNA genome of approximately 8 kb. The HPVs have similar genome organizations, with regulatory functions encoded by the early (E) genes and structural components encoded by the late (L) genes (reviewed in reference 24). HPVs of different types differ in DNA sequences by 10% or more in the L1 gene, and the other viral genes exhibit a greater degree of sequence diversity between types (6, 15). Papillomaviruses are grouped into genera based on their L1 gene sequences and are further subdivided into species, with most of the HPVs in genus alpha or genus beta. The genus alpha HPVs infect the mucosal epithelium, and those that are the etiological agent responsible for the development of anogenital cancers (including cervical cancer) fall into genus alpha, species 7, and genus alpha, species 9. Beta-type HPVs infect the cutaneous epithelium.The HPV E6 protein has long been appreciated as a critical regulator of the viral life cycle and driver of tumorigenesis for the high-risk HPVs. Through the action of the HPV E7 protein, the G 1 -S checkpoint is bypassed in infected cells by the inactivation of the retinoblastoma tumor suppressor protein (pRB1) (17,18,46). This results in a cellular environment that is conducive to the replication of the viral DNA but in which proapoptotic signals have been triggered. One crucial function of high-risk HPV E6 proteins is to counteract the effects of p53 following this trigger, and this is accomplished by the targeted ubiquitylati...

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Viral Perturbations of Host Networks Reflect Disease Etiology

Cited by 103 publications

References 49 publications

Human symptoms–disease network

Human symptoms–disease network

Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

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