scholarly journals Virus-host protein-protein interactions between human papillomavirus 16 E6 A1 and D2/D3 sub-lineages: variances and similarities

2020 ◽  
Author(s):  
Guillem Dayer ◽  
Mehran L. Masoom ◽  
Melissa Togtema ◽  
Ingeborg Zehbe
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Asian American ◽  
Protein Interactions ◽  
Host Protein ◽  
Cellular Proteins ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
E6 Protein

AbstractHigh-risk strains of human papillomavirus are causative agents for cervical and other mucosal cancers with type 16 being the most frequent. Compared to the European Prototype (A1, denoted “EP”), the Asian-American (D2/D3, denoted “AA”) sub-lineage or “variant” is reported to have increased abilities to promote carcinogenesis. Few global interactome studies have looked at protein-protein interactions (PPIs) between host proteins and variants of the key transforming E6 protein. We applied a primary human foreskin keratinocyte model transduced with EP and AA variant E6 genes and co-immunoprecipitated expressed E6 proteins along with interacting cellular proteins to detect virus-host binding partners. We reasoned that, due to single nucleotide polymorphisms, AAE6 and EPE6 may have unique PPIs with host cellular proteins—conferring gain or loss of function—resulting in varied abilities to promote carcinogenesis. Using liquid chromatography-mass spectrometry and stringent interactor selection criteria based on the number of peptides, we identified 25 candidates: 6 unique to each of AAE6 and EPE6, along with 13 E6 targets common to both AAE6 and EPE6. We also applied a more inclusive process based on pathway selection and discovered 171 target proteins: 90 unique AAE6 and 61 unique EPE6 along with 20 common E6 targets between the two sub-lineages. Interpretations for both approaches were made using databases such as UniProt, BioGRID and Reactome. Detected E6 targets are implicated in important hallmarks of cancer: deregulating Notch and other signaling, energetics and hypoxia, DNA replication and repair, and immune response. Validation experiments, such as reverse co-immunoprecipitation and RNA interference, are required to substantiate these findings. Here, we provide an unprecedented resource for new research questions in HR HPV biology. The current data also underline our lab’s driving hypothesis that E6, being a “master regulator” in HPV-positive cancers, is an excellent candidate for anti-cancer treatment strategies.Author SummaryChronic infection with high-risk human papillomavirus (HPV) type 16 is the most prevalent cause of cervical and other mucosal cancers. The E6 oncoproteins of the European Prototype (EP) and the Asian-American (AA) HPV variants differentially promote carcinogenesis. We looked at protein-protein interactions between host proteins and two key HPV variant E6 proteins of these strains to reveal how high risk HPVs cause cancer, based on the proteins they bind to in infected cells. Our methodology combined molecular biology and data mining techniques using widely available databases. We confirmed and discovered novel virus-host associations that explained how HPV AA and EP variants differ in their carcinogenic capabilities, and confirmed the candidacy of the E6 protein as a viable target for HPV therapies.

scholarly journals Virus–Host Protein–Protein Interactions between Human Papillomavirus 16 E6 A1 and D2/D3 Sub-Lineages: Variances and Similarities

2020 ◽  
Vol 21 (21) ◽  
pp. 7980
Author(s):  
Guillem Dayer ◽  
Mehran L. Masoom ◽  
Melissa Togtema ◽  
Ingeborg Zehbe
Keyword(s):  
Human Papillomavirus ◽  
Asian American ◽  
Protein Interactions ◽  
Host Protein ◽  
Cellular Proteins ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Human Papillomavirus 16 ◽  
Novel Approach ◽  
Causative Agents

High-risk strains of human papillomavirus are causative agents for cervical and other mucosal cancers, with type 16 being the most frequent. Compared to the European Prototype (EP; A1), the Asian-American (AA; D2/D3) sub-lineage seems to have increased abilities to promote carcinogenesis. Here, we studied protein–protein interactions (PPIs) between host proteins and sub-lineages of the key transforming E6 protein. We transduced human keratinocyte with EP or AA E6 genes and co-immunoprecipitated E6 proteins along with interacting cellular proteins to detect virus–host binding partners. AAE6 and EPE6 may have unique PPIs with host cellular proteins, conferring gain or loss of function and resulting in varied abilities to promote carcinogenesis. Using liquid chromatography-mass spectrometry and stringent interactor selection criteria based on the number of peptides, we identified 25 candidates: 6 unique to AAE6 and EPE6, along with 13 E6 targets common to both. A novel approach based on pathway selection discovered 171 target proteins: 90 unique AAE6 and 61 unique EPE6 along with 20 common E6 targets. Interpretations were made using databases, such as UniProt, BioGRID, and Reactome. Detected E6 targets were differentially implicated in important hallmarks of cancer: deregulating Notch signaling, energetics and hypoxia, DNA replication and repair, and immune response.

scholarly journals The SMC5/6 Complex Interacts with the Papillomavirus E2 Protein and Influences Maintenance of Viral Episomal DNA

2018 ◽  
Vol 92 (15) ◽  
Author(s):  
Peris Bentley ◽  
Min Jie Alvin Tan ◽  
Alison A. McBride ◽  
Elizabeth A. White ◽  
Peter M. Howley
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Protein Interactions ◽  
Persistent Infection ◽  
Viral Genome ◽  
Host Protein ◽  
Cellular Proteins ◽  
Genome Maintenance ◽  
Viral Dna ◽  
E2 Protein

ABSTRACTThe papillomavirus E2 protein executes numerous essential functions related to viral transcription, replication of viral DNA, and viral genome maintenance. Because E2 lacks enzymatic activity, many of these functions are mediated by interactions with host cellular proteins. Unbiased proteomics approaches have successfully identified a number of E2-host protein interactions. We have extended such studies and have identified and validated the cellular proteins structural maintenance of chromosome 5 (SMC5) and SMC6 as interactors of the viral E2 protein. These two proteins make up the core components of the SMC5/6 complex. The SMC5/6 complex is a member of the conserved structural maintenance of chromosomes (SMC) family of proteins, which are essential for genome maintenance. We have examined the role of SMC5/6 in various E2 functions. Our data suggest that SMC6 is not required for E2-mediated transcriptional activation, E1/E2-mediated transient replication, or differentiation-dependent amplification of viral DNA. Our data, however, suggest a role for SMC5/6 in viral genome maintenance.IMPORTANCEThe high-risk human papillomaviruses (HPVs) are the etiological cause of cervical cancer and the most common sexually transmitted infection. While the majority of infections may be asymptomatic or cause only benign lesions, persistent infection with the oncogenic high-risk HPV types may lead to serious diseases, such as cervical cancer, anogenital carcinoma, or head and neck oropharyngeal squamous cell carcinoma. The identification of virus-host protein interactions provides insights into the mechanisms of viral DNA persistence, viral genome replication, and cellular transformation. Elucidating the mechanism of early events in the virus replication cycle as well as of integration of viral DNA into host chromatin may present novel antiviral strategies and targets for counteracting persistent infection. The E2 protein is an important viral regulatory protein whose functions are mediated through interactions with host cell proteins. Here we explore the interaction of E2 with SMC5/6 and the functional consequences.

scholarly journals Different Subtypes of Influenza Viruses Target Different Human Proteins and Pathways Leading to Different Pathogenic Phenotypes

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Yujie Wang ◽  
Ting Song ◽  
Kaiwu Li ◽  
Yuan Jin ◽  
Junjie Yue ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Viral Proteins ◽  
Influenza Viruses ◽  
Host Protein ◽  
Protein Protein Interactions ◽  
Influenza A Viruses ◽  
Host Proteins ◽  
Pathogenic Mechanisms ◽  
Human Proteins

Different subtypes of influenza A viruses (IAVs) cause different pathogenic phenotypes after infecting human bodies. Analysis of the interactions between viral proteins and the host proteins may provide insights into the pathogenic mechanisms of the virus. In this paper, we found that the same proteins (nucleoprotein and neuraminidase) of H1N1 and H5N1 have different impacts on the NF-κB activation. By further examining the virus–host protein–protein interactions, we found that both NP and NA proteins of the H1N1 and H5N1 viruses target different host proteins. These results indicate that different subtypes of influenza viruses target different human proteins and pathways leading to different pathogenic phenotypes.

scholarly journals Viruses.STRING: A virus–host protein–protein interaction database

2018 ◽  
Author(s):  
Helen Victoria Cook ◽  
Nadezhda Tsankova ◽  
Damian Szklarczyk ◽  
Christian von Mering ◽  
Lars Juhl Jensen
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Host Protein ◽  
Interaction Data ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Host Interactions ◽  
Protein Protein Interaction ◽  
Interaction Database ◽  
Protein Interaction Database

AbstractAs viruses continue to pose risks to global health, having a better un-derstanding of virus–host protein–protein interactions aids in the development of treatments and vaccines. Here, we introduce Viruses.STRING, a protein–protein interaction database specifically catering to virus-virus and virus-host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app.

scholarly journals Viruses.STRING: A Virus-Host Protein-Protein Interaction Database

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 519 ◽  
Author(s):  
Helen Cook ◽  
Nadezhda Doncheva ◽  
Damian Szklarczyk ◽  
Christian von Mering ◽  
Lars Jensen
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Host Protein ◽  
Interaction Data ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Host Interactions ◽  
Protein Protein Interaction ◽  
Interaction Database ◽  
Protein Interaction Database

As viruses continue to pose risks to global health, having a better understanding of virus–host protein–protein interactions aids in the development of treatments and vaccines. Here, we introduce Viruses.STRING, a protein–protein interaction database specifically catering to virus–virus and virus–host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app.

scholarly journals Genetic and Molecular Characterization of the Caenorhabditis elegans Gene, mel-26, a Postmeiotic Negative Regulator of MEI-1, a Meiotic-Specific Spindle Component

Genetics ◽  
1998 ◽  
Vol 150 (1) ◽  
pp. 119-128
Author(s):  
M Rhys Dow ◽  
Paul E Mains
Keyword(s):  
Caenorhabditis Elegans ◽  
Protein Interactions ◽  
Negative Regulator ◽  
Meiotic Spindle ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Gain Of Function ◽  
Recessive Mutations ◽  
Female Germline

Abstract We have previously described the gene mei-1, which encodes an essential component of the Caenorhabditis elegans meiotic spindle. When ectopically expressed after the completion of meiosis, mei-1 protein disrupts the function of the mitotic cleavage spindles. In this article, we describe the cloning and the further genetic characterization of mel-26, a postmeiotic negative regulator of mei-1. mel-26 was originally identified by a gain-of-function mutation. We have reverted this mutation to a loss-of-function allele, which has recessive phenotypes identical to the dominant defects of its gain-of-function parent. Both the dominant and recessive mutations of mel-26 result in mei-1 protein ectopically localized in mitotic spindles and centrosomes, leading to small and misoriented cleavage spindles. The loss-of-function mutation was used to clone mel-26 by transformation rescue. As suggested by genetic results indicating that mel-26 is required only maternally, mel-26 mRNA was expressed predominantly in the female germline. The gene encodes a protein that includes the BTB motif, which is thought to play a role in protein-protein interactions.

scholarly journals The Human Papillomavirus Type 31 Late 3′ Untranslated Region Contains a Complex Bipartite Negative Regulatory Element

2002 ◽  
Vol 76 (12) ◽  
pp. 5993-6003 ◽  
Author(s):  
Sarah A. Cumming ◽  
Claire E. Repellin ◽  
Maria McPhillips ◽  
Jonathan C. Radford ◽  
J. Barklie Clements ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Papillomavirus ◽  
High Risk ◽  
Epithelial Cells ◽  
Regulatory Element ◽  
Capsid Proteins ◽  
Cellular Proteins ◽  
Late Gene Expression ◽  
Hpv 16 ◽  
Negative Regulatory Element

ABSTRACT The papillomavirus life cycle is tightly linked to epithelial cell differentiation. Production of virus capsid proteins is restricted to the most terminally differentiated keratinocytes in the upper layers of the epithelium. However, mRNAs encoding the capsid proteins can be detected in less-differentiated cells, suggesting that late gene expression is controlled posttranscriptionally. Short sequence elements (less than 80 nucleotides in length) that inhibit gene expression in undifferentiated epithelial cells have been identified in the late 3′ untranslated regions (UTRs) of several papillomaviruses, including the high-risk mucosal type human papillomavirus type 16 (HPV-16). Here we show that closely related high-risk mucosal type HPV-31 also contains elements that can act to repress gene expression in undifferentiated epithelial cells. However, the HPV-31 negative regulatory element is surprisingly complex, comprising a major inhibitory element of approximately 130 nucleotides upstream of the late polyadenylation site and a minor element of approximately 110 nucleotides mapping downstream. The first 60 nucleotides of the major element have 68% identity to the negative regulatory element of HPV-16, and these elements bind the same cellular proteins, CstF-64, U2AF65, and HuR. The minor inhibitory element binds some cellular proteins in common with the major inhibitory element, though it also binds certain proteins that do not bind the upstream element.

scholarly journals Bacteria Use Structural Imperfect Mimicry To Hijack The Host Interactome

2020 ◽  
Author(s):  
Natalia Sanchez de Groot ◽  
Marc Torrent Burgas
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Eukaryotic Proteins ◽  
Host Pathogen ◽  
Imperfect Mimicry ◽  
The Way

ABSTRACTBacteria use protein-protein interactions to infect their hosts and hijack fundamental pathways, which ensures their survival and proliferation. Hence, the infectious capacity of the pathogen is closely related to its ability to interact with host proteins. Here, we show that hubs in the host-pathogen interactome are isolated in the pathogen network by adapting the geometry of the interacting interfaces. An imperfect mimicry of the eukaryotic interfaces allows pathogen proteins to actively bind to the host’s target while preventing deleterious effects on the pathogen interactome. Understanding how bacteria recognize eukaryotic proteins may pave the way for the rational design of new antibiotic molecules.

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