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Reconstructing the ubiquitin network: cross-talk with other systems and identification of novel functions.

Venancio TM, Balaji S, Iyer LM, Aravind L - Genome Biol. (2009)

Bottom Line: We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics.Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA. venancit@ncbi.nlm.nih.gov

ABSTRACT

Background: The ubiquitin system (Ub-system) can be defined as the ensemble of components including Ub/ubiquitin-like proteins, their conjugation and deconjugation apparatus, binding partners and the proteasomal system. While several studies have concentrated on structure-function relationships and evolution of individual components of the Ub-system, a study of the system as a whole is largely lacking.

Results: Using numerous genome-scale datasets, we assemble for the first time a comprehensive reconstruction of the budding yeast Ub-system, revealing static and dynamic properties. We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.

Conclusions: Using these representations, evidence is provided for the functional diversification of components such as SUMO-dependent Ub-ligases. We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics. We present evidence for a major impact of the Ub-system on large parts of the proteome via its interaction with the transcription regulatory network. Furthermore, the dynamics of the Ub-network suggests that Ub and SUMO modifications might function cooperatively with transcription control in regulating cell-cycle-stage-specific complexes and in reinforcing periodicities in gene expression. Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

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Reconstructed network using PMI. Graphical representation of the network structure captured by calculating PMI based on protein presence in cliques. Subgraphs representing important biological processes are inside boxes and magnified: APC complex (A); sumoylation pathway (B); Golgi and vesicles (C); proteasome (D); splicing (E); Skp1 and signalosome (F); ERAD (G); peroxisome (H). The colors are the same as in Figure 1. The layout of the graph to group together functionally linked dense subgraphs was achieved using the edge-weighted spring embedded (Kamada-Kawai) algorithm, which has previously been shown to be very effective for such depictions [113].
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Figure 5: Reconstructed network using PMI. Graphical representation of the network structure captured by calculating PMI based on protein presence in cliques. Subgraphs representing important biological processes are inside boxes and magnified: APC complex (A); sumoylation pathway (B); Golgi and vesicles (C); proteasome (D); splicing (E); Skp1 and signalosome (F); ERAD (G); peroxisome (H). The colors are the same as in Figure 1. The layout of the graph to group together functionally linked dense subgraphs was achieved using the edge-weighted spring embedded (Kamada-Kawai) algorithm, which has previously been shown to be very effective for such depictions [113].

Mentions: To further investigate the biological significance of cliques, we devised a novel method of identifying high-confidence functional interactions between nodes using a measure that has been termed point-wise or specific mutual information (PMI) of co-occurrence in cliques (see Materials and methods for details). We consequently identified 1,077 high confidence interactions (P ≤ 0.005) between 258 Ub/Ubl pathway components and represented this as a graph (Figure 5; Table S2 in Additional data file 1). This graph shows a striking structure with several densely connected subgraphs that are likely to represent major functional ensembles with biological significance (Figure 4). As a positive control we checked these densely connected graphs for several previously identified complexes and found that they were faithfully recovered. Examples of these include the entire proteasomal complex with the associated DUBs and ubiquitin receptors, the signalosome, the APC complex, the ubiquitin-dependent regulatory system of peroxisomal import, and the urmylation, neddylation and sumoylation pathways. We also obtained independent corroboration for many of these linkages in the form of their co-occurrence in the clusters generated by the MCL technique.


Reconstructing the ubiquitin network: cross-talk with other systems and identification of novel functions.

Venancio TM, Balaji S, Iyer LM, Aravind L - Genome Biol. (2009)

Reconstructed network using PMI. Graphical representation of the network structure captured by calculating PMI based on protein presence in cliques. Subgraphs representing important biological processes are inside boxes and magnified: APC complex (A); sumoylation pathway (B); Golgi and vesicles (C); proteasome (D); splicing (E); Skp1 and signalosome (F); ERAD (G); peroxisome (H). The colors are the same as in Figure 1. The layout of the graph to group together functionally linked dense subgraphs was achieved using the edge-weighted spring embedded (Kamada-Kawai) algorithm, which has previously been shown to be very effective for such depictions [113].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691004&req=5

Figure 5: Reconstructed network using PMI. Graphical representation of the network structure captured by calculating PMI based on protein presence in cliques. Subgraphs representing important biological processes are inside boxes and magnified: APC complex (A); sumoylation pathway (B); Golgi and vesicles (C); proteasome (D); splicing (E); Skp1 and signalosome (F); ERAD (G); peroxisome (H). The colors are the same as in Figure 1. The layout of the graph to group together functionally linked dense subgraphs was achieved using the edge-weighted spring embedded (Kamada-Kawai) algorithm, which has previously been shown to be very effective for such depictions [113].
Mentions: To further investigate the biological significance of cliques, we devised a novel method of identifying high-confidence functional interactions between nodes using a measure that has been termed point-wise or specific mutual information (PMI) of co-occurrence in cliques (see Materials and methods for details). We consequently identified 1,077 high confidence interactions (P ≤ 0.005) between 258 Ub/Ubl pathway components and represented this as a graph (Figure 5; Table S2 in Additional data file 1). This graph shows a striking structure with several densely connected subgraphs that are likely to represent major functional ensembles with biological significance (Figure 4). As a positive control we checked these densely connected graphs for several previously identified complexes and found that they were faithfully recovered. Examples of these include the entire proteasomal complex with the associated DUBs and ubiquitin receptors, the signalosome, the APC complex, the ubiquitin-dependent regulatory system of peroxisomal import, and the urmylation, neddylation and sumoylation pathways. We also obtained independent corroboration for many of these linkages in the form of their co-occurrence in the clusters generated by the MCL technique.

Bottom Line: We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics.Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA. venancit@ncbi.nlm.nih.gov

ABSTRACT

Background: The ubiquitin system (Ub-system) can be defined as the ensemble of components including Ub/ubiquitin-like proteins, their conjugation and deconjugation apparatus, binding partners and the proteasomal system. While several studies have concentrated on structure-function relationships and evolution of individual components of the Ub-system, a study of the system as a whole is largely lacking.

Results: Using numerous genome-scale datasets, we assemble for the first time a comprehensive reconstruction of the budding yeast Ub-system, revealing static and dynamic properties. We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.

Conclusions: Using these representations, evidence is provided for the functional diversification of components such as SUMO-dependent Ub-ligases. We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics. We present evidence for a major impact of the Ub-system on large parts of the proteome via its interaction with the transcription regulatory network. Furthermore, the dynamics of the Ub-network suggests that Ub and SUMO modifications might function cooperatively with transcription control in regulating cell-cycle-stage-specific complexes and in reinforcing periodicities in gene expression. Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

Show MeSH
Related in: MedlinePlus