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. 2010 May 14;4:63.
doi: 10.1186/1752-0509-4-63.

Construction of a Large Scale Integrated Map of Macrophage Pathogen Recognition and Effector Systems

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Free PMC article

Construction of a Large Scale Integrated Map of Macrophage Pathogen Recognition and Effector Systems

Sobia Raza et al. BMC Syst Biol. .
Free PMC article

Abstract

Background: In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.

Results: The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.

Conclusions: The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.

Figures

Figure 1
Figure 1
Pathway construction workflow. A workflow diagram summarizing the main stages of pathway assembly from concept to final diagram. Blue boxes portray the pathway construction phase. Each phase embodies a number of tasks (shown as lilac boxes or yellow-ellipses for data storage and processing), which when completed lead to progression towards the next stage of pathway construction (connected by green arrows). Red arrows indicate feedback to a previous construction phase. Lilac boxes describe the construction steps required pre-pathway assembly, whereas green boxes are linked to post-construction phases and describe the possible applications of the constructed and validated pathway diagram.
Figure 2
Figure 2
Integrated pathway diagram of innate immune and macrophage activation pathways. The modified Edinburgh Pathway Notation (mEPN) scheme is used to describe the interactions of signalling pathways active in the macrophage. A total of 2,172 components in this network are connected by 2,553 edges. Components include 496 unique proteins, the complexes formed between them (412), 181 genes/DNA/promotor regions, in addition to other molecular species (e.g. pathogens, drugs, RNA) and the nodes representing the processes in which the components are involved. Components are arranged to reflect the location in which they are active and background colour is used to distinguish between different sub-cellular locations.
Figure 3
Figure 3
(a) Breakdown of node class in the integrated pathway diagram and (b) Key to the pathway layout and content of the integrated diagram. (a) Components, Boolean Logic, Process Nodes and Edge Annotation form the category of possible nodes. A detailed breakdown of the number of each type of node in each category is given. (b) The key reflects the approximate location of the different pathway modules depicted in the integrated diagram (Figure 2). Ideally pathways with high connectivity and sharing identical components are spatially located in close proximity.
Figure 4
Figure 4
Snapshots from the integrated macrophage pathway diagram. (a) Activation of the interferon type-1 receptor through its interaction with interferon-α (IFNA) or interferon-β (IFNB1). In each case binding of the ligand causes autophosphorylation of JAK1 which eventually leads to the type1-interferon response (not shown). (b) Activation of TLR7 by single stranded RNA in the endosome. This sequential multistep process involves binding events, autophosphorylations and dissociations steps. (c) E3 ligase system. Up to 500 proteins may potentially function as E3 ligases and here the well documented members are shown. (d) Depiction of the proteasome. In some cases it is useful to lay out the subunits of a complex to reflect the complexes known structure. Represented here are the layers of the proteasome's barrel structure and cap. (e) Activation of MAPK14 (p38). Phosphorylation of p38 is reversible; numerous kinases will phosphorylate p38. p38 is dephosphorylated by DUSP1 and inhibited by the specific inhibitor SB203580. (f) Combinatorial assembly of the MHC class 2 HLA-D (alpha/beta) complexes. The & and OR Boolean operators indicate the combinatorial assembly of HLA-D (alpha/beta) complex from different classes of MHC class 2 proteins. (g) Genes activated by NFKB1 (p50):RELA (p65) complex. A number of genes activated by the binding of the p50:p65 complex to known NFKB elements in their promoter. In each case the likely functional consequence of this activation is shown as a pathway output. (h) Regulation of IFNB1 expression. Shown are the known promoter elements and factors that bind to them leading to IFNB1 expression.
Figure 5
Figure 5
Overlay of Ifn-β timecourse analysis onto the macrophage pathway using BioLayout Express3D. Views of regions of the macrophage pathway where components were found to be regulated Ifn-β. Components regulated at the level of gene expression are enlarged and coloured according to their cluster membership. All non-regulated components and other nodes are grey. (a) Regulation of Toll Like Receptor Signalling. All endosomal TLRs, Myd88 and Tifa genes are induced from 1 h, their expression being maximally up-regulated at 4-8 h post-Ifn-β treatment. (b) Regulation of death-receptor and apoptosis signalling. The expression of all regulated components in this module rises from 1 h and reaches a maximum 2-4 h post-treatment. In contrast, the expression of the anti-apoptotic gene Bcl2 is suppressed at 4 h. (c) Regulation of the transcriptional targets of interferon signalling. 7 genes (shown in yellow) belong to cluster 2 and their expression induced from 1 h, becoming maximal at 4 h. 4 genes (in purple) were in cluster 3, with expression rising from 1 h and remaining maximal throughout 4-8 h post-treatment. Irf1 (in green) reaches maximal expression at 2 h. (d) Regulation of type I and type II interferon signalling. All receptor components, except Ifngr1, belong to clusters of induced genes. Socs1 and Socs3 are induced and reach maximal expression at early time points (1-2 or 2 h).

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