InnateDB: facilitating systems-level analyses of the mammalian innate immune response.

Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB (www.innatedb.ca) has been developed to facilitate systems-level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity-relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user-supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems-oriented manner.

Curating the innate immunity interactome.

BACKGROUND: The innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http://www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity. RESULTS: Here, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response. CONCLUSIONS: In summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity.

Gliotactin and Discs large form a protein complex at the tricellular junction of polarized epithelial cells in Drosophila.

The tricellular junction (TCJ) forms at the convergence of pleated septate junctions (SJs) from three adjacent cells in polarized epithelia and is necessary for maintaining the transepithelial barrier. In Drosophila, the transmembrane protein Gliotactin was the first identified marker of the TCJ, but little is known about other molecular constituents. We now show that Gliotactin associates with Discs large at the TCJ in a Ca(2+)-dependent manner. Discs large is essential for the formation of the TCJ and the localization of Gliotactin. Surprisingly, Gliotactin localization at the TCJ was independent of its PDZ-binding motif and Gliotactin did not bind directly to Discs large. Therefore Gliotactin and Discs large association is through intermediary proteins at the TCJ. Gliotactin can associate with other septate junction proteins but this was detected only when Gliotactin was overexpressed and spread throughout the septate junction domain. Gliotactin overexpression and spread also resulted in a reduction of Discs large staining but not vice versa. These results suggest that Discs large participates in different protein interactions in the SJ and the TCJ. Finally this work supports a model where Gliotactin and Dlg are components of a larger protein complex that links the converging SJs with the TCJ to create the transepithelial barrier.