ComPPI: a cellular compartment-specific database for protein–protein interaction network analysis

Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.

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“…Alternatively, they may act in distinct cell types, or subcellular locations (68). They may also cooperate to remove the Ub chains from TRAF6.…”

Section: Cyldmentioning

confidence: 99%

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Guven-Maiorov

Keskin

Gürsoy

et al. 2015

Biophysical Journal

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“…ComPPI is an integrated database of protein subcellular localization and protein-protein interactions from multiple databases including BioGRID, CCSB, DIP, HPRD, IntAct and MatrixDB. [88]. The highly confident interactomes of each member of the dual specificity phosphatase family for Homo sapiens were fetched from comPPI, filtering for localization score and interaction score thresholds of 0.7 each.…”

Section: Baseline Dusp Interactomementioning

confidence: 99%

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Subbannayya

Pinto

Bösl

et al. 2019

Preprint

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Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focused on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSPmediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study has the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

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“…The bacterial proteins can be provided by the user, either from experiments,publicly available datasets or bioinformatic predictions. Resources which are currently used in the MicrobioLink pipeline to compile the human proteins are ComPPI [35], MatrixDB [36] and Human Protein Atlas (HPA) [37]. The user can also provide their own pre-compiled lists of proteins.…”

Section: Pipeline Descriptionmentioning

confidence: 99%

MicrobioLink: An integrated computational pipeline to infer functional effects of microbiome-host interactions

Andrighetti

Bohár

Lemke

et al. 2019

Preprint

Self Cite

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Microbiome-host interactions are important to nearly all living organisms, and play important roles in health and disease. Understanding these interkingdom cross-talks has a huge potential to advance diverse scientific domains such as the clinical and medical sciences, agriculture, and ecology. Detecting such interactions by experimental techniques remain challenging from a cost and feasibility perspective thus hampering large-scale analyses. Computational approaches not only make the inference of microbiome-host interactions viable but also scalable. Here, we present MicrobioLink, a computational pipeline to integrate predicted interactions between microbial and host proteins with host molecular networks. With MicrobioLink users can analyse how microbial proteins in a certain context are influencing cellular processes by interacting with host proteins and affecting downstream pathways, regulating gene expression and metabolism. To show the applicability of the pipeline, we used Crohn's disease metaproteomic data and compared the predictions from the pipeline with those from the healthy condition to demonstrate the achievability of a potential model showing how the influence of microbial proteins can potentially influence disease developments. MicrobioLink is a freely available on GitHub.Code availability: https://github.com/korcsmarosgroup/HMIpipeline

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ComPPI: a cellular compartment-specific database for protein–protein interaction network analysis

Cited by 137 publications

References 53 publications

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

A Structural View of Negative Regulation of the Toll-like Receptor-Mediated Inflammatory Pathway

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

MicrobioLink: An integrated computational pipeline to infer functional effects of microbiome-host interactions

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