Nucleic Acids Research Advance Access originally published online on October 30, 2008
Nucleic Acids Research 2009 37(Database issue):D669-D673; doi:10.1093/nar/gkn739
Nucleic Acids Research, 2009, Vol. 37, Database issue D669-D673
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
VirusMINT: a viral protein interaction database
Andrew Chatr-aryamontri1,
Arnaud Ceol1,
Daniele Peluso1,2,
Aurelio Nardozza1,
Simona Panni3,
Francesca Sacco1,
Michele Tinti1,
Alex Smolyar4,
Luisa Castagnoli1,
Marc Vidal4,
Michael E. Cusick4 and
Gianni Cesareni1,2,*
1Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, 2IRCCS Fondazione Santa Lucia, 00143 Rome, 3Department of Cell Biology, University of Calabria, Via P. Bucci, Rende (CS) Italy and 4Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
*To whom correspondence should be addressed. Tel: +39 0672594315; Fax: +39 062023500; Email: cesareni{at}uniroma2.it
Received August 13, 2008. Revised September 20, 2008. Accepted October 2, 2008.
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ABSTRACT
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Understanding the consequences on host physiology induced by
viral infection requires complete understanding of the perturbations
caused by virus proteins on the cellular protein interaction
network. The VirusMINT database (
http://mint.bio.uniroma2.it/virusmint/)
aims at collecting all protein interactions between viral and
human proteins reported in the literature. VirusMINT currently
stores over 5000 interactions involving more than 490 unique
viral proteins from more than 110 different viral strains. The
whole data set can be easily queried through the search pages
and the results can be displayed with a graphical viewer. The
curation effort has focused on manuscripts reporting interactions
between human proteins and proteins encoded by some of the most
medically relevant viruses: papilloma viruses, human immunodeficiency
virus 1, Epstein–Barr virus, hepatitis B virus, hepatitis
C virus, herpes viruses and Simian virus 40.
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INTRODUCTION
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Viruses interfere with fundamental cellular processes, such
as gene expression, cell growth and differentiation, by perturbing
the cellular regulatory networks. The molecular mechanisms underlying
this subversion of cell physiology mediated by viral infection
can be understood only by uncovering how viral proteins perturb
cellular protein interaction networks.
Elucidating mechanisms of viral action may thus be better achieved within an interpretative framework relying not on individual genes, but rather on entire biological pathways and networks. Although cellular protein interaction maps already exist for a few model organisms, and recent efforts have been made in order to compile from public databases viral interactions maps (1), there is currently no resource archiving and publicly providing exhaustive and detailed interaction maps between viral and host proteins, with the possible exception of the HIV-1 Human Protein Interactions Database (http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions) and of the PIG database (http://pig.vbi.vt.edu).
VirusMINT fills this gap by collecting and annotating, in a structured format, all interactions reported in the scientific literature between viral and host proteins (mainly human).
Although several automation proposals have been put forward to increase the efficiency and accuracy of curation (2), manual curation is, to date, the best way to populate databases with high-quality data.
The curation efforts to date has concentrated mainly on viruses known to be associated with infectious diseases and oncogenesis in humans, such as adenovirus, Simian virus 40 (SV40), human papilloma viruses, Epstein–Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV) and herpes viruses. Future plans include regular update of the data set and its extension to new viruses.
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DATA CURATION
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Protein–protein interactions were manually curated from
the literature or imported from other databases: MINT (
3), IntAct
(
4) and HIV-1 Human Protein Interactions Database. Data uploaded
from MINT and Intact did not require any extra curation effort,
as these databases fully describe the interaction details in
their entries, reporting relevant information including interaction
detection method, experimental role of interactors and participant
identification method. Furthermore these two databases already
have adopted PSI-MI standards (
5), greatly facilitating data
management. The HIV-1 Human Protein Interactions Database does
not conform to PSI-MI standards and does not provide a full
description of experimental details, only the functional relationship
between the interaction partners. Thus, only a subset of interactions
reported in the HIV-1 Human Protein Interactions Database data
set could be imported, namely those representing enzymatic reactions,
physical associations and co-localization. These interactions
were automatically remapped to the most appropriate term in
the PSI-MI controlled vocabulary (
Table 1).
Interaction data derived from articles curated according to
the IMEx manual were first uploaded in MINT and then reimported
in VirusMINT while, in order to rapidly populate VirusMINT with
new viral interactions, we also applied a quick curation strategy,
conforming to MIMIx standards (
6) but without reporting the
full experimental details substantiating each interaction. Each
interaction is thus described by the experimental method, the
interaction type and the experimental roles of the interactors,
as defined by the PSI-MI ontology. Interacting proteins were
remapped from NCBI identifiers to UniprotKB identifiers (
7)
wherever possible using the PICR service (
8).
To distinguish between viral proteins generated from the same precursor (and which therefore point to the same Uniprot KB accession number), we took advantage of a new term, polyprotein fragment, recently introduced in the PSI-MI ontology. Distinct polyprotein fragments are annotated with their name, the range of the protein with respect to the polyprotein precursor and the ‘polyprotein fragment’ ontology term. Each fragment is considered and displayed in VirusMINT as a distinct molecule.
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DATA SELECTION
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To select relevant articles from the literature we developed
a simple text mining script. The implemented parser, based on
‘context free grammar’, identifies sentences containing
interaction information (
9). We first searched PubMed for abstracts
containing virus names. Each sentence in the selected abstracts
was then individually examined for presence of interaction keywords,
which were largely based on the list of Temkin and Gilder (
9).
To further increase efficiency of the parser this list was enriched
with new tags, based mainly on the methods most commonly used
for the identification of protein–protein interactions,
and with the name list of the viral proteins of interest.
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DATA SEARCH
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Whereas it is possible to perform a quick search based on protein
or gene name, or based on an identifier from external databases
from the VirusMINT home page, the ‘Advanced Search page’
allows for more flexible queries based on criteria such as the
viral data set of interest (
Figure 1) or a publication reference
(PubMed ID number or DOI identifier). The search returns a list
of proteins, and by clicking on the protein name the browser
will present in the left frame a summary of the Uniprot Knowledgebase
record for the selected protein, and in the right frame the
list of interacting partners. Interactions involving proteins
obtained from the processing of the same viral polyprotein are
considered as distinct in VirusMINT. Each interaction is also
assigned a confidence score (
10). A summary of the reported
interactions with related experimental details can be accessed
by clicking on the number in the ‘interactions’
column.
View larger version (26K):
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Figure 1. The Advanced Search page showing search options. VirusMINT can be queried for protein or gene name and for various database identifiers. Queries can be restricted to a strain of interest by clicking the corresponding radio button. The bottom half of the page lists all viruses represented in the database, and clicking on the corresponding virus name returns a graph of all interactions between viral and human proteins.
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VISUALIZATION
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The ‘VirusMINT viewer’ button launches a Java applet
that shows a graph of all interaction partners for that protein
(
Figure 2a). Node size is proportional to the molecular weight
of the protein and node color is used to distinguish different
species. Proteins linked to OMIM (
11) diseases are highlighted
in red. Edges are weighted according the number of supporting
experimental evidences. The graph displayed by the VirusMINT
viewer can be expanded (left click on ‘+’), or edited
interactively by moving or deleting nodes (right click). The
‘score’ scroll bar is used to filter interactions
according to a user-defined confidence threshold. In the interactome
viewer, the confidence score takes into account the interactions
involving proteins in all the strains of a particular virus.
Finally, the ‘connect’ button interrogates the MINT
database to add all the interactions between the proteins displayed
in the graph (
Figure 2b).
View larger version (32K):
[in this window]
[in a new window]
[Download PowerPoint slide]
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Figure 2. The VirusMINT viewer. (a) By clicking on the VirusMINT viewer button all the interactions of the protein of interest will be displayed as a graph. (b) The ‘connect’ button interrogates the MINT database for all interactions between the proteins displayed in the graph.
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VirusMINT also provides an innovative graphic display to visualize
the full interactome of a given virus. This function is available
both from the Homepage and from the Advanced Search Page, where
it is also possible to restrict the query to a single viral
strain. If no strain is specified, ortholog proteins from each
strain are grouped to provide a ‘collapsed’ unique
interactome for all available viral data. The interactome viewer
displays both virus–virus and virus–host interactions.
For smaller interactomes, the MINT database is queried for non-viral
proteins to provide additional connections in the virus–host
graph. The interactome viewer launches as a compact interface,
where proteins are represented by dots rather than circles,
and where all viral proteins are easily identifiable in red
font. It is possible to switch to the classic viewer representation
by scrolling the appropriate bar. A mouse click on a virus node
triggers the display on the left frame of all strains in which
orthologs of the protein are represented in VirusMINT. Clicking
the edges displays a summary of the experimental evidences of
the selected interaction. For both the ‘?’ button
will open a pop-up window with detailed information about the
selected protein.
‘Extension buttons’ found in the MINT viewer have not been implemented in the VirusMINT viewer, since VirusMINT viewer already displays all available data about the interactome of the selected virus.
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DATA SUBMISSION
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Authors of publications reporting protein interactions involving
viral proteins are encouraged to submit the interaction data
directly to VirusMINT. From the download page it is possible
to obtain a preformatted spreadsheet file containing instructions
for the compilation of the different fields.
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STATISTICS
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VirusMINT contains interaction data for 557 proteins encoded
by 149 different viral strains, corresponding to 2007 unique
interactions supported by 5483 experimental evidences derived
from more than 1690 articles. Currently, 477 articles describing
1415 unique interactions supported by 2635 experimental evidences
were manually curated in addition to the imported interactions
(
Table 2).
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DATA DOWNLOAD
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The VirusMINT data set is freely available and can be obtained
by clicking the ‘Download’ link on the VirusMINT
homepage. It is released in two different formats: flat files
and PSI-2.5 XML files.
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FUNDING
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Associazione Italiana per la Ricerca sul Cancro; ENFIN Network
of Excellence (LSHG-CT-2005-518254); Dana-Farber Cancer Institute
Strategic Initiative; National Human Genome Research Institute
(P50-HG004233); and National Institute of Environmental Health
Science (R01-ES015728
[GenBank]
). Funding for open access charge: XXX.
Conflict of interest statement. None declared.
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Footnotes
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The authors wish it to be known that, in their opinion, the
first two authors should be regarded as joint First Authors.
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REFERENCES
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